Glycoside derivatives and uses thereof

ABSTRACT

The present invention provides a compound of formula I; 
                         
a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a metabolic disorder characterized by recurrent orpersistent hyperglycemia (high blood glucose) and other signs, asdistinct from a single disease or condition. Glucose level abnormalitiescan result in serious long-term complications, which includecardiovascular disease, chronic renal failure, retinal damage, nervedamage (of several kinds), microvascular damage and obesity.

Type 1 diabetes, also known as Insulin Dependent Diabetes Mellitus(IDDM), is characterized by loss of the insulin-producing β-cells of theislets of Langerhans of the pancreas leading to a deficiency of insulin.Type-2 diabetes previously known as adult-onset diabetes, maturity-onsetdiabetes, or Non-Insulin Dependent Diabetes Mellitus (NIDDM)—is due to acombination of increased hepatic glucose output, defective insulinsecretion, and insulin resistance or reduced insulin sensitivity(defective responsiveness of tissues to insulin).

Chronic hyperglycemia can also lead to onset or progression of glucosetoxicity characterized by decrease in insulin secretion from β-cell,insulin sensitivity; as a result diabetes mellitus is self-exacerbated[Diabetes Care, 1990, 13, 610].

Chronic elevation of blood glucose level also leads to damage of bloodvessels. In diabetes, the resultant problems are grouped under“microvascular disease” (due to damage of small blood vessels) and“macrovascular disease” (due to damage of the arteries). Examples ofmicrovascular disease include diabetic retinopathy, neuropathy andnephropathy, while examples of macrovascular disease include coronaryartery disease, stroke, peripheral vascular disease, and diabeticmyonecrosis.

Diabetic retinopathy, characterized by the growth of weakened bloodvessels in the retina as well as macular edema (swelling of the macula),can lead to severe vision loss or blindness. Retinal damage (frommicroangiopathy) makes it the most common cause of blindness amongnon-elderly adults in the US. Diabetic neuropathy is characterized bycompromised nerve function in the lower extremities. When combined withdamaged blood vessels, diabetic neuropathy can lead to diabetic foot.Other forms of diabetic neuropathy may present as mononeuritis orautonomic neuropathy. Diabetic nephropathy is characterized by damage tothe kidney, which can lead to chronic renal failure, eventuallyrequiring dialysis. Diabetes mellitus is the most common cause of adultkidney failure worldwide. A high glycemic diet (i.e., a diet thatconsists of meals that give high postprandial blood sugar) is known tobe one of the causative factors contributing to the development ofobesity.

Type 2 diabetes is characterized by insulin resistance and/or inadequateinsulin secretion in response to elevated glucose level. Therapies fortype 2 diabetes are targeted towards increasing insulin sensitivity(such as TZDs), hepatic glucose utilization (such as biguanides),directly modifying insulin levels (such as insulin, insulin analogs, andinsulin secretagogues), increasing incretin hormone action (such asexenatide and sitagliptin), or inhibiting glucose absorption from thediet (such as alpha glucosidase inhibitors) [Nature 2001, 414, 821-827].

Glucose is unable to diffuse across the cell membrane and requirestransport proteins. The transport of glucose into epithelial cells ismediated by a secondary active cotransport system, the sodium-D-glucoseco-transporter (SGLT), driven by a sodium-gradient generated by theNa+/K+-ATPase. Glucose accumulated in the epithelial cell is furthertransported into the blood across the membrane by facilitated diffusionthrough GLUT transporters [Kidney International 2007, 72, S27-S35].

SGLT belongs to the sodium/glucose co-transporter family SLCA5. Twodifferent SGLT isoforms, SGLT1 and SGLT2, have been identified tomediate renal tubular glucose reabsorption in humans [Curr. Opinon inInvestigational Drugs (2007): 8(4), 285-292 and references citedherein]. Both of them are characterized by their different substrateaffinity. Although both of them show 59% homology in their amino acidsequence, they are functionally different. SGLT1 transports glucose aswell as galactose, and is expressed both in the kidney and in theintestine, while SGLT2 is found exclusively in the S1 and S2 segments ofthe renal proximal tubule. As a consequence, glucose filtered in theglomerulus is reabsorbed into the renal proximal tubular epithelialcells by SGLT2, a low-affinity/high-capacity system, residing on thesurface of epithelial cell lining in S1 and S2 tubular segments. Muchsmaller amounts of glucose are recovered by SGLT1, as ahigh-affinity/low-capacity system, on the more distal segment of theproximal tubule. In healthy human, more than 99% of plasma glucose thatis filtered in the kidney glomerulus is reabsorbed, resulting in lessthan 1% of the total filtered glucose being excreted in urine. It isestimated that 90% of total renal glucose absorption is facilitated bySGLT2; remaining 10% is likely mediated by SGLT1 [J. Parenter. EnteralNutr. 2004, 28, 364-371].

SGLT2 was cloned as a candidate sodium glucose co-transporter, and itstissue distribution, substrate specificity, and affinities arereportedly very similar to those of the low-affinity sodium glucoseco-transporter in the renal proximal tubule. A drug with a mode ofaction of SGLT2 inhibition will be a novel and complementary approach toexisting classes of medication for diabetes and its associated diseasesto meet the patient's needs for both blood glucose control, whilepreserving insulin secretion. In addition, SGLT2 inhibitors which leadto loss of excess glucose (and thereby excess calories) may haveadditional potential for the treatment of obesity.

Indeed small molecule SGLT2 inhibitors have been discovered and theanti-diabetic therapeutic potential of such molecules has been reportedin literature [T-1095 (Diabetes, 1999, 48, 1794-1800, Dapagliflozin(Diabetes, 2008, 57, 1723-1729)].

Various O-aryl and O-heteroaryl glycosides have been reported as SGLT-2inhibitors in patent publications such as: WO 01/74834, WO 03/020737,U.S. Ser. No. 04/0018998, WO 01/68660, WO 01/16147, WO 04/099230, WO05/011592, U.S. Ser. No. 06/0293252 and WO 05/021566.

Various glucopyranosyl-substituted aromatic and heteroaromatic compoundshave also been reported as SGLT-2 inhibitors in patent publications suchas: WO 01/27128, WO 04/080990, U.S. Ser. No. 06/0025349, WO 05/085265,WO 05/085237, WO 06/054629 and WO 06/011502.

SGLT1 is predominantly found in the intestine and plays a major role inthe absorption of D-glucose and D-galactose. Therefore, SGLT1 inhibitorshave the potential to act both in the kidney as well as the intestine toreduce calorie intake and hyperglycemia.

WO2004/018491 discloses pyrazole derivatives which are SGLT1 inhibitors.Glucopyranosyl-substituted aromatic or heteroaromatic compounds where,in general, the sugar moiety has been modified at C4, C5, or C6positions of pyranose have been published (U.S. Ser. No. 06/0009400,U.S. Ser. No. 06/0019948, U.S. Ser. No. 06/0035841, U.S. Ser. No.06/0074031, U.S. Ser. No. 08/002,7014 and WO 08/016,132).

Prodrug strategies or methodologies can be used to markedly enhanceproperties of a drug or to overcome an inherent deficiency in thepharmaceutical or pharmacokinetic properties of a drug. Prodrugs are newchemical entities which, upon administration to the patient, regeneratesthe parent molecule within the body. Prodrugs can provide choices inmodulating the conditions for regeneration of a parent drug and formodulating the physical, pharmaceutic, or pharmacokinetic properties ofthe parent drug. However, the identification of prodrugs with desiredproperties is often difficult.

SUMMARY OF THE INVENTION

The invention therefore provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   ring A is a 5-, 6- or 7-membered heterocyclyl;    -   X is O, NR⁵, S, S(O) or S(O)₂;    -   V is hydrogen, halo or —OR^(1b);    -   R¹, R^(1a) and R^(1b) are independently selected from the group        consisting of hydrogen, C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl,        —C(O)C₆₋₁₀aryl and —C(O)C₁₋₆alkyl;    -   R² and R^(2a), for each occurrence, are independently selected        from the group consisting of halo, hydroxy, cyano, carboxy,        C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₁₀cycloalkyl;    -   R³ is halo, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₁₀cycloalkyl,        C₁₋₆alkoxy, haloC₁₋₃alkoxy or a 3- to 7-membered heterocyclyl;    -   R⁴ is a C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, or        a 5- to 10-membered heteroaryl;    -   R⁵ is hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, or C₁₋₆alkanoyl; or    -   R⁴ and R⁵ together with the nitrogen to which they are attached        form a 3- to 7-membered heterocyclyl;    -   n is 0, 1, 2, or 3; and    -   q is 0, 1, or 2.

Compounds of the invention are useful for treating diseases andconditions mediated by the sodium D-glucose co-transporter (SGLT), e.g.hyperglycemia, diabetes, and the like. The invention also providesmethods of treating such diseases and conditions, and compounds andcompositions etc. for their treatment.

The compounds of the invention possess sodium-D-glucose co-transporter(SGLT) inhibition effects, which are beneficial for the prophylaxis,management, treatment, control of progression, or adjunct treatment ofdiseases and/or medical conditions where the inhibition of SGLT would bebeneficial, such as diabetes (including Type-I and Type-II),hyperglycemia, obesity, dyslipidemia, insulin resistance, and othermetabolic syndrome, and/or diabetes-related complications includingretinopathy, nephropathy, neuropathy, ischemic heart disease,arteriosclerosis, β-cell dysfunction, and as therapeutic and/orprophylactic agents for obesity.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless specified otherwise, the term “compounds of the presentinvention” refers to compounds of Formula (I) (including the examples),and salts (preferably pharmaceutically acceptable salts) thereof, aswell as all stereoisomers (including diastereoisomers and enantiomers),tautomers and isotopically labeled compounds of formula (I) (e.g.,deuterium substitutions), as well as inherently formed moieties (e.g.,polymorphs, solvates and/or hydrates).

The requisite number of carbon atoms for groups such as alkyl, alkoxy,aryl, etc., is represented as C₁₋₆, C₁₋₄, etc. in the definitions below.For example, a C₁₋₆alkoxy has from one to six carbon atoms and aC₁₋₁₀heteroaryl has from one to 10 carbon atoms.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 20carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbonatoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, orn-decyl.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein that is substituted by one or more halo groups as defined herein.The haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkylincluding perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloroor fluoro within the alkyl group. Dihaloalky and polyhaloalkyl groupscan have two or more of the same halo atoms or a combination ofdifferent halo groups within the alkyl. Typically the polyhaloalkylcontains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. A perhaloalkyl refers to an alkyl having all hydrogenatoms replaced with halo atoms.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain,having from one to twelve carbon atoms, preferably one to 6 carbonatoms, and linking the rest of the molecule to a radical group. Examplesof alkylene groups include methylene, ethylene, propylene, n-butylene,and the like. The alkylene is attached to the rest of the moleculethrough a single bond and to the radical group through a single bond.The points of attachment of the alkylene to the rest of the molecule andto the radical group can be through one carbon or any two carbons withinthe chain.

“Halogen” or “halo” may be fluoro, chloro, bromo or iodo.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. Preferably, alkoxy groups have about 1-6, more preferablyabout 1-4 carbons.

As used herein, the term “haloalkoxy” refers to an alkoxy as definedherein that is substituted by one or more halo groups as defined herein.The haloalkoxy can be monohaloalkoxy, dihaloalkoxy or polyhaloalkoxyincluding perhaloalkoxy. A monohaloalkoxy can have one iodo, bromo,chloro or fluoro within the alkoxy group. Dihaloalkoxy andpolyhaloalkoxy groups can have two or more of the same halo atoms or acombination of different halo groups within the alkoxy. Typically thepolyhaloalkoxy contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2halo groups. Non-limiting examples of haloalkyl include fluoromethoxy,difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy,trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy,difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy,difluoropropoxy, dichloroethoxy and dichloropropoxy. A perhaloalkoxyrefers to an alkoxy having all hydrogen atoms replaced with halo atoms.

As used herein, the term “alkanoyl” refers to alkyl-C(O)—, wherein alkylis defined herein above. Representative examples of alkanoyl groupsinclude, but are not limited to, acetyl, propionyl, butyryl,3-isobutyryl, pentanoyl and the like. Preferably, alkanoyl groups haveabout 1-6, more preferably about 1-4 carbons.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-10 carbon atoms in the ring portion. Examples includephenyl and naphthyl.

The term “aryl” also refers to a group in which a aryl ring is fused toone or more non-aromatic carbocyclyl provided that at least one ring inthe ring system is aromatic. Nonlimiting examples include2,3-dihydro-1H-inden-5-yl and 1,2,3,4-tetrahydronaphth-2-yl.

The term “arylalkyl” refers to an aryl group which is linked to anothermoiety via an alkylene group which may be branched or unbranched.Examples of arylalkyl groups include benzyl, 2-phenyl-ethyl,2-(naphth-2-yl)-butan-1-yl, and the like.

As used herein, the term “heterocyclyl” refers to an optionallysubstituted, saturated or unsaturated non-aromatic ring or ring system,e.g., which is a 3,4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-,10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or15-membered tricyclic ring system and contains at least one heteroatomselected from O, S and N, where the N and S can also optionally beoxidized to various oxidation states. The heterocyclic group can beattached at a heteroatom or a carbon atom. The heterocyclyl can includefused or bridged rings as well as spirocyclic rings. Examples ofheterocycles include dihydrofuranyl, [1,3]dioxolanyl, 1,4-dioxanyl,1,4-dithianyl, piperazinyl, 1,3-dioxolanyl, imidazolidinyl,imidazolinyl, pyrrolidinyl, dihydropyranyl, oxathiolanyl, dithiolanyl,1,3-dioxanyl, 1,3-dithianyl, oxathianyl, thiomorpholinyl, oxiranyl,aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,tetrahydropyranyl, piperidinyl, morpholinyl, azepinyl, oxapinyl,oxazepinyl and diazepinyl.

As used herein, the term “carbocyclyl” refers to saturated or partiallyunsaturated (but not aromatic) monocyclic, bicyclic or tricyclichydrocarbon groups of 3-12 carbon atoms, preferably 3-9, or 3-7 carbonatoms, Exemplary monocyclic hydrocarbon groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl or cyclohexenyl. Exemplary bicyclic hydrocarbon groupsinclude bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,or bicyclo[2.2.2]octyl. Exemplary tricyclic hydrocarbon groups includeadamantyl. A “cycloalkyl” is a carbocyclyl that is completely saturated.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or polycyclic-aromatic ring system having 1 to8 heteroatoms selected from N, O or S and at least one carbon atom,preferably from 1-10, more preferably from 1-6 carbon atoms, in the ringsystem. Preferably, the heteroaryl is a 5-10 or 5-7 membered ringsystem. Examples of monocyclic heteroaryl groups include pyridyl,thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl andtetrazolyl. Examples of bicyclic heteroaryl groups include indolyl,benzofuranyl, isoquinolinyl indazolyl, indolinyl, isoindolyl,indolizinyl, benzamidazolyl, and quinolinyl.

The term “heteroaryl” also refers to a group in which an aromatic ringis fused to one or more non-aromatic carbocyclyl or heterocyclylprovided that at least one ring in the ring system is aromatic and atleast one ring contains a heteroatom, for example,3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl and1,2,3,4-tetrahydroquinolin-7-yl.

A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic.

The term “heteroarylalkyl” refers to an heteroaryl group which is linkedto another moiety via an alkylene group which may be branched orunbranched. Examples of heteroarylalkyl groups include2-(pyridin-3-yl)-ethyl, 3-(quinolin-7-yl)-butan-1-yl, and the like.

“Heteroaryl” and “heterocyclyl” is also intended to include oxidized Sor N, such as sulfinyl, sulfonyl and N-oxide of tertiary ring nitrogen.

Unless indicated explicitly otherwise, where combinations of groups arereferred to herein as one moiety, e.g. arylalkyl, the last mentionedgroup contains the atom by which the moiety is attached to the rest ofthe molecule.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable.

The present invention contemplates various stereoisomers and mixturesthereof and includes “enantiomers”, which refers to two stereoisomerswhose molecules are non-superimposeable mirror images of one another.

Compounds of the invention may exist in one or more geometrical,optical, enantiomeric, diastereomeric and tautomeric forms, includingbut not limited to cis- and trans-forms, E- and Z-forms, R-, S- andmeso-forms, keto-, and enol-forms. All such isomeric forms are includedwithin the invention. The isomeric forms may be in isomerically pure orenriched form, as well as in mixtures of isomers (e.g. racemic ordiastereomeric mixtures).

Accordingly, the invention provides:

-   -   stereoisomeric mixtures of compounds of Formula (I);    -   a diastereomerically enriched or diastereomerically pure isomer        of a compound of Formula (I); or    -   an enantiomerically enriched or enantiomerically pure isomer of        a compound of Formula (I).

Where appropriate isomers can be separated from their mixtures by theapplication or adaptation of known methods (e.g. chromatographictechniques and recrystallisation techniques). Where appropriate isomerscan be prepared by the application or adaptation of known methods (e.g.asymmetric synthesis).

Unless otherwise indicated, the present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as HPLC using a chiralcolumn. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts”. The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates or solvates,which include solvents used for their crystallization. The compounds ofthe present invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

By way of clarity, compounds of the invention included all isotopes ofthe atoms present in formula (I) and any of the examples or embodimentsdisclosed herein. For example, H (or hydrogen) represents any isotopicform of hydrogen including ¹H, ²H(D), and ³H(T); C represents anyisotopic form of carbon including ¹²C, ¹³C, and ¹⁴C; O represents anyisotopic form of oxygen including ¹⁶O, ¹⁷O and ¹⁸O; N represents anyisotopic form of nitrogen including ¹³N, ¹⁴N and ¹⁵N; P represents anyisotopic form of phosphorous including ³¹P and ³²P; S represents anyisotopic form of sulfur including ³²S and ³⁵S; F represents any isotopicform of fluorine including ¹⁹F and ¹⁸F; Cl represents any isotopic formof chlorine including ³⁵Cl, ³⁷Cl and ³⁶Cl; and the like. In a preferredembodiment, compounds represented by formula (I) comprises isomers ofthe atoms therein in their naturally occurring abundance. However, incertain instances, it is desirable to enrich one or more atom in aparticular isotope which would normally be present in less abundance.For example, ¹H would normally be present in greater than 99.98%abundance; however, a compound of the invention can be enriched in ²H or³H at one or more positions where H is present. In particularembodiments of the compounds of formula (I), when, for example, hydrogenis enriched in the deuterium isotope, the symbol “D” may be used torepresent the enrichment in deuterium. In one embodiment, when acompound of the invention is enriched in a radioactive isotope, forexample ³H and ¹⁴C, the compound may be useful in drug and/or substratetissue distribution assays. Likewise, enrichment with positron emittingisotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in PositronEmission Topography (PET) studies for examining substrate receptoroccupancy. It is to be understood that the invention encompasses allsuch isotopic forms which inhibit SGLT.

Isotopically-enriched compounds of Formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described herein using an appropriateisotopically-enriched reagent in place of the non-enriched reagentpreviously employed.

Compounds of the invention, i.e. compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalforms include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter, for example blood sugar), orboth. In yet another embodiment, “treat”, “treating” or “treatment”refers to preventing or delaying the onset or development or progressionof the disease or disorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

The amount of the compound of the invention administered should be atherapeutically effective amount where the compound or derivative isused for the treatment of a disease or condition or symptom thereof, anda prophylactically effective amount where the compound or derivative isused for the prevention of a disease or condition or a symptom thereof.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviate, inhibit,prevent and/or ameliorate a condition or a disease, or a symptomthereof, wherein the condition or disease, or symptom thereof, is (i)mediated by SGLT1 and/or SGLT2, (ii) associated with SGLT1 and/or SGLT2activity, (iii) characterized by activity (normal or abnormal) of SGLT1and/or SGLT2; or (2) alleviated by reducing or inhibiting the activityof SGLT1 and/or SGLT2. In another non-limiting embodiment, the term “atherapeutically effective amount” refers to the amount of the compoundof the present invention that, when administered to a cell, or a tissue,or a non-cellular biological material, or a medium, is effective to atleast partially reducing or inhibiting the activity of SGLT1 and/orSGLT2; or at least partially reducing or inhibiting the expression ofSGLT1 and/or SGLT2. The exact dosage will generally be dependent on thepatient's status at the time of administration. Factors that may betaken into consideration when determining dosage include the severity ofthe disease state in the patient, the general health of the patient, theage, weight, gender, diet, time, frequency and route of administration,drug combinations, reaction sensitivities and the patient's tolerance orresponse to therapy. The precise amount can be determined by routineexperimentation, but may ultimately lie with the judgement of theclinician. Generally, an effective dose will be from 0.01 mg/kg/day(mass of drug compared to mass of patient) to 1000 mg/kg/day, e.g. 1mg/kg/day to 100 mg/kg/day or 1 mg/kg/day to 10 mg/kg/day. Compositionsmay be administered individually to a patient or may be administered incombination with other agents, drugs or hormones.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians. As usedherein, the term “disorder” is synonymous with “condition”.

The term “comprising” encompasses “including” as well as “consisting”,e.g. a composition “comprising” X may consist exclusively of X or mayinclude something additional, e.g. X+Y.

The word “substantially” does not exclude “completely” e.g. acomposition which is “substantially free” from Y may be completely freefrom Y. Where necessary, the word “substantially” may be omitted fromthe definition of the invention.

The term “about” in relation to a numerical value x means, for example,x+10′)/0.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

Unless it is explicitly stated that a group is substituted or mayoptionally be substituted, it is to be understood that the group isunsubstituted.

Compounds of the Invention

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

In one embodiment, the invention provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   ring A is a 5-, 6- or 7-membered heterocyclyl;    -   X is O, NR^(S), S, S(O) or S(O)₂;    -   V is hydrogen, halo or —OR^(1b);    -   R¹, R^(1a) and R^(1b) are independently selected from the group        consisting of hydrogen, C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl,        —C(O)C₆₋₁₀aryl and —C(O)C₁₋₆alkyl;    -   R² and R^(2a), for each occurrence, are independently selected        from the group consisting of halo, hydroxy, cyano, carboxy,        C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₁₀cycloalkyl;    -   R³ is halo, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₁₀cycloalkyl,        C₁₋₆alkoxy, haloC₁₋₃alkoxy or a 3- to 7-membered heterocyclyl;    -   R⁴ is a C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, or        a 5- to 10-membered heteroaryl;    -   R⁵ is hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, or C₁₋₆alkanoyl; or    -   R⁴ and R⁵ together with the nitrogen to which they are attached        form a 3- to 7-membered heterocyclyl;    -   n is 0, 1, 2, or 3; and    -   q is 0, 1, or 2.

In one embodiment the invention provides compounds of formula (I), or apharmaceutically acceptable salt thereof, wherein the group representedby the following formula:

is selected from the group consisting of:

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein the grouprepresented by the following formula:

is selected from the group consisting of:

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein the grouprepresented by the following formula:

is selected from the group consisting of:

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein the grouprepresented by the following formula:

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein n is 0.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein q is 0.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein V is —OR^(1b).

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein R¹, R^(1a), andR^(1b) are hydrogen.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein R³ is halo,C₁₋₆alkyl, or C₃₋₁₀cycloalkyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein R³ is bromo,ethyl or cyclopropyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein R³ is ethyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein X is O.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein X is S.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein X is S(O)₂.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein R⁴ is C₁₋₄alkyl,haloC₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl, or a 5- to 6-membered heteroaryl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein R⁴ is methyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein X is NR⁵.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein R⁴ is a C₁₋₆alkyland R⁵ is a C₁₋₆alkanoyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein R⁴ is n-propyland R⁵ is acetyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein R⁴ and R⁵together with the nitrogen to which they are attached form a 5- to6-membered heterocyclyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein R⁴ and R⁵together with the nitrogen to which they are attached form a pyrrolidinoor a morpholino.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein:

-   -   the group represented by the following formula:

-   -   is selected from the group consisting of:

-   -   X is O, S, or S(O)₂;    -   V is —OR^(1b);    -   R¹, R^(1a), and R^(1b) are hydrogen;    -   R³ is halo, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl; and    -   R⁴ is a C₁₋₄alkyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein:

-   -   the group represented by the following formula:

-   -   is selected from the group consisting of:

-   -   X is O;    -   V is —OR^(1b);    -   R¹, R^(1a), and R^(1b) are hydrogen;    -   R³ is halo, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl; and    -   R⁴ is a C₁₋₄alkyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein:

-   -   the group represented by the following formula:

-   -   is selected from the group consisting of:

-   -   X is S;    -   V is —OR^(1b);    -   R¹, R^(1a), and R^(1b) are hydrogen;    -   R³ is halo, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl; and    -   R⁴ is a C₁₋₄alkyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein:

-   -   the group represented by the following formula:

-   -   is selected from the group consisting of:

-   -   X is S(O)₂;    -   V is —OR^(1b);    -   R¹, R^(1a), and R^(1b) are hydrogen;    -   R³ is halo, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl; and    -   R⁴ is a C₁₋₄alkyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein:

-   -   the group represented by the following formula:

-   -   is selected from the group consisting of:

-   -   X is O, S, or S(O)₂;    -   V is —OR^(1b);    -   R¹, R^(1a), and R^(1b) are hydrogen;    -   R³ is bromo, ethyl or cyclopropyl; and    -   R⁴ is methyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein:

-   -   the group represented by the following formula:

-   -   is selected from the group consisting of:

-   -   X is NR⁵;    -   V is —OR^(1b);    -   R¹, R^(1a), and R^(1b) are hydrogen;    -   R³ is halo, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl;    -   R⁴ is a C₁₋₄alkyl; and    -   R⁵ is a C₁₋₄alkanoyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein:

-   -   the group represented by the following formula:

-   -   is selected from the group consisting of:

-   -   X is NR⁵;    -   V is —OR^(1b);    -   R¹, R^(1a), and R^(1b) are hydrogen;    -   R³ is halo, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl; and    -   R⁴ and R⁵, together with the nitrogen atom to which they are        attached, form a 3- to 7-membered heterocyclyl.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:

-   (2S,3R,4R,5S)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-isochroman-7-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Ethyl-3-isochroman-7-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methanesulfonyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methanesulfonyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   N-[(3S,4R,5R,6S)-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-3,4,5-trihydroxy-tetrahydro-pyran-2-yl]-N-propyl-acetamide;-   2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]thiepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol-   (2S,3R,4R,5S,6R)-2-[4-Ethyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-Zethylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Methoxy-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopentyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclobutyl-3-(2,3,4,5-tetrahydro-benzo[b]thiepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2R,3S,4R,5R,6S)-2-Methylsulfanyl-6-[4-oxetan-3-yl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-cyclopropyl-3-((3,4-dihydro-spiro[benzo[b][1,4]oxazine-2,1′-cyclopropane]-6-yl)methyl)phenyl)-6-(methylsulfonyl)tetrahydro-2H-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(1,1-dioxo-1,2,3,4-tetrahydro-1lambda*6*-benzo[1,4]thiazin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopentyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2R,3S,4R,5R,6S)-2-Methanesulfonyl-6-[4-oxetan-3-yl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[3-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-ethyl-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Ethyl-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(3,4-dihydro-2H-1,4-ethano-quinolin-7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Ethyl-3-(1,2,3,4-tetrahydro-quinoxalin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   6-[2-Cyclopropyl-5-((2S,3R,4R,5S,6S)-3,4,5-tri    hydroxy-6-methoxy-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid;-   6-[2-Cyclopropyl-5-((2S,3R,4R,5S,6S)-3,4,5-tri    hydroxy-6-methoxy-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonitrile;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(5-methylamino-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3S,4R,5R,6S)-2-Meth    oxy-6-[4-oxetan-3-yl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(2,3,4,5-tetra    hydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(2,3,4,5-tetra    hydro-benzo[b]thiepin-7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Ethyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methoxy-tetra    hydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Chloro-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methoxy-tetra    hydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylmethyl)-phenyl]-6-methoxy-tetra    hydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-phenylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-(thiophene-2-sulfonyl)-tetra    hydro-pyran-3,4,5-triol;-   (3S,4R,5R,6S)-2-Cyclopropanesulfonyl-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-3,4,5-triol;    and-   (2S,3R,4R,5S)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-(2,2,2-trifluoro-ethanesulfonyl)tetrahydro-pyran-3,4,5-triol.

In another embodiment the invention provides compounds of formula (I),or a pharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:

-   (2S,3R,4R,5S)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-isochroman-7-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Ethyl-3-isochroman-7-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methanesulfonyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methanesulfonyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;    and-   (2S,3R,4R,5S,6S)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol.

In another embodiment, the variables in formula (I) are those defined bythe groups in the Examples section below.

In another embodiment individual compounds according to the inventionare those listed in the Examples section below.

Treatment of Diseases and Conditions

Compounds of Formula (I) have been found to be inhibitors of SGLT. Asused herein, inhibition of SGLT means inhibition exclusively of SGLT2,inhibition exclusively of SGLT1 or inhibition of both SGLT1 and SGLT2.

The invention provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for use in therapy. The invention furtherprovides a pharmaceutical composition comprising a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in combination witha pharmaceutically acceptable excipient.

The invention further provides a method for the treatment of a diseaseor condition mediated by the sodium D-glucose co-transporter, comprisingthe step of administering a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to a subject. The invention also provides the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a disease or conditionmediated by the sodium D-glucose co-transporter. The invention alsoprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, for use in treating a disease or condition mediated by thesodium D-glucose co-transporter.

The SGLT inhibitory activity of the compounds of the invention may bedemonstrated by the SGLT2 and SGLT1 assays disclosed hereinbelow.Preferred compounds of the invention have an IC₅₀ in the SGLT2 assay of<100 nM, in one embodiment <30 nM, in one embodiment <20 nM, in oneembodiment <10 nM, in another embodiment <5 nM, and in anotherembodiment <1 nM, and in another embodiment <0.5 nM. In anotherembodiment, preferred compounds of the invention have an IC₅₀ in theSGLT1 assay of <10,000 nM, in one embodiment <1500 nM, in one embodiment<1000 nM, in one embodiment <700 nM, in another embodiment <500 nM andin another embodiment <200 nM.

The present invention also provides a method of treating diabetescomprising administering a compound of Formula (I), or apharmaceutically acceptable salt thereof, to a subject in need thereof.

In another embodiment, the invention provides a method of treating adisease or condition mediated by the sodium D-glucose co-transporter ina mammal, comprising administering to the mammal in need thereof atherapeutically effective amount of a compound according to formula (I),or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are useful as both prophylacticand therapeutic treatments for diseases or conditions related to theinhibition of SGLT-2 and/or SGLT-1.

1. Diseases and Conditions Mediated by the Sodium D-GlucoseCo-Transporter

The invention is useful for the treatment of a disease or disordermediated by the sodium D-glucose co-transporter. Diseases and conditionsmediated by the sodium D-glucose co-transporter include: metabolicdisorders, retinopathy, nephropathy, diabetic foot, ulcers,macroangiopathies, metabolic acidosis or ketosis, reactivehypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulinresistance, metabolic syndrome (such as dyslipidemia, obesity, insulinresistance, hypertension, microalbuminemia, hyperuricaemia, andhypercoagulability), dyslipidaemias of different origins,atherosclerosis and related diseases, high blood pressure, chronic heartfailure, edema, hyperuricaemia, Syndrome X, diabetes, insulinresistance, decreased glucose tolerance (also known as impaired glucosetolerance, IGT), non-insulin-dependent diabetes mellitus, Type IIdiabetes, Type I diabetes, diabetic complications, body weightdisorders, weight loss, body mass index and leptin related diseases. Inone embodiment, the diseases and conditions include metabolic syndrome(such as dyslipidemia, obesity, insulin resistance, hypertension,microalbuminemia, hyperuricaemia, and hypercoagulability), Syndrome X,diabetes, insulin resistance, decreased glucose tolerance (also known asimpaired glucose tolerance, IGT), non-insulin-dependent diabetesmellitus, Type II diabetes, Type I diabetes, diabetic complications,body weight disorders, weight loss, body mass index and leptin relateddiseases. In one embodiment, the disease or disorder is decreasedglucose tolerance, Type II diabetes or obesity.

Compounds of formula (I), or a pharmaceutically acceptable salt thereof,may be also suitable for preventing beta-cell degeneration such asapoptosis or necrosis of pancreatic beta cells, for improving orrestoring the functionality of pancreatic cells, increasing the numberand size of pancreatic beta cells, for use as diuretics orantihypertensives and for the prevention and treatment of acute renalfailure.

As a further aspect, the invention relates to a method for treating adisorder selected from type I and type II diabetes mellitus,complications of diabetes, comprising administration of an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

As used herein a patient is suffering from “obesity” if the patientexhibits at least one of:

-   -   a body mass index (BMI), i.e. the patient's mass (in kg) divided        by the square of the patient's height (in m), of 30 or more;    -   an absolute waist circumference of >102 cm in men or >88 cm in        women;    -   a waist-to-hip ratio>0.9 in men or >0.85 in women; or    -   a percent body fat >25% in men or >30% in women.

As used herein a patient is suffering from “Type II diabetes” if theymeet the World Health Organisation criteria for Diabetes diagnosis(Definition and diagnosis of diabetes mellitus and intermediatehyperglycaemia, WHO, 2006), i.e. the patient exhibits at least one of:

-   -   a fasting plasma glucose ≧7.0 mmol/l (126 mg/dl); or    -   a venous plasma glucose ≧11.1 mmol/l (200 mg/dl) 2 hours after        ingestion of 75 g oral glucose load.

As used herein a patient is suffering from “IGT” if they meet the WorldHealth Organisation criteria for IGT diagnosis (Definition and diagnosisof diabetes mellitus and intermediate hyperglycaemia, WHO, 2006), i.e.the patient exhibits both of:

-   -   a fasting plasma glucose ≧7.0 mmol/l (126 mg/dl); and    -   a venous plasma glucose ≧7.8 and <11.1 mmol/l (200 mg/dl) 2        hours after ingestion of 75 g oral glucose load.        Administration & Formulation        1. General

For pharmaceutical use, the compounds of the invention may beadministered as a medicament by enteral or parenteral routes, includingintravenous, intramuscular, subcutaneous, transdermal, airway (aerosol),oral, intranasal, rectal, vaginal and topical (including buccal andsublingual) administration. The compounds of Formula (I) should beassessed for their biopharmaceutical properties, such as solubility andsolution stability (across pH), permeability, etc., in order to selectthe most appropriate dosage form and route of administration fortreatment of the proposed indication. In one embodiment the compoundsare administered orally.

The compounds of the invention may be administered as crystalline oramorphous products. The compounds of the invention may be administeredalone or in combination with one or more other compounds of theinvention or in combination with one or more other drugs (or as anycombination thereof). Generally, they will be administered as aformulation in association with one or more pharmaceutically acceptableexcipients. The term “excipient” includes any ingredient other than thecompound(s) of the invention which may impart either a functional (e.gdrug release rate controlling) and/or a non-functional (e.g. processingaid or diluent) characteristic to the formulations. The choice ofexcipient will to a large extent depend on factors such as theparticular mode of administration, the effect of the excipient onsolubility and stability, and the nature of the dosage form.

The present invention provides a pharmaceutical composition comprising acompound according to Formula (I), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.

Typical pharmaceutically acceptable excipients or carriers include:

-   -   diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol,        cellulose and/or glycine;    -   lubricants, e.g. silica, talcum, stearic acid, its magnesium or        calcium salt and/or polyethyleneglycol;    -   binders, e.g. magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone;    -   disintegrants, e.g. starches, agar, alginic acid or its sodium        salt, or effervescent mixtures; and/or    -   absorbants, colorants, flavors and/or sweeteners.

A thorough discussion of pharmaceutically acceptable excipients isavailable in Gennaro, Remington: The Science and Practice of Pharmacy2000, 20th edition (ISBN: 0683306472).

Accordingly, in one embodiment, the present invention provides apharmaceutical composition comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carrier.

2. Oral Administration

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, and/or buccal, lingual, or sublingualadministration by which the compound enters the blood stream directlyfrom the mouth.

Formulations suitable for oral administration include solid plugs, solidmicroparticulates, semi-solid and liquid (including multiple phases ordispersed systems) such as tablets; soft or hard capsules containingmulti- or nano-particulates, liquids (e.g. aqueous solutions), emulsionsor powders; lozenges (including liquid-filled); chews; gels; fastdispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesivepatches.

Formulations suitable for oral administration may also be designed todeliver the compounds of Formula (I) in an immediate release manner orin a rate-sustaining manner, wherein the release profile can be delayed,pulsed, controlled, sustained, or delayed and sustained or modified insuch a manner which optimises the therapeutic efficacy of the saidcompounds. Means to deliver compounds in a rate-sustaining manner areknown in the art and include slow release polymers that can beformulated with the said compounds to control their release.

Examples of rate-sustaining polymers include degradable andnon-degradable polymers that can be used to release the said compoundsby diffusion or a combination of diffusion and polymer erosion. Examplesof rate-sustaining polymers include hydroxypropyl methylcellulose,hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodiumcarboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone,xanthum gum, polymethacrylates, polyethylene oxide and polyethyleneglycol.

Liquid (including multiple phases and dispersed systems) formulationsinclude emulsions, suspensions, solutions, syrups and elixirs. Suchformulations may be presented as fillers in soft or hard capsules (made,for example, from gelatin or hydroxypropylmethylcellulose) and typicallycomprise a carrier, for example, water, ethanol, polyethylene glycol,propylene glycol, methylcellulose, or a suitable oil, and one or moreemulsifying agents and/or suspending agents. Liquid formulations mayalso be prepared by the reconstitution of a solid, for example, from asachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in Liang andChen, Expert Opinion in Therapeutic Patents 2001, 11(6): 981-986.

The formulation of tablets is discussed in H. Lieberman and L. Lachman,Pharmaceutical Dosage Forms Tablets 1980, vol. 1 (Marcel Dekker, NewYork).

3. Parenteral Administration

The compounds of the invention can be administered parenterally.

The compounds of the invention may be administered directly into theblood stream, into subcutaneous tissue, into muscle, or into an internalorgan. Suitable means for administration include intravenous,intraarterial, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular, intrasynovial andsubcutaneous. Suitable devices for administration include needle(including microneedle) injectors, needle-free injectors and infusiontechniques.

Parenteral formulations are typically aqueous or oily solutions. Wherethe solution is aqueous, excipients such as sugars (including butrestricted to glucose, mannitol, sorbitol, etc.) salts, carbohydratesand buffering agents (preferably to a pH of from 3 to 9), but, for someapplications, they may be more suitably formulated as a sterilenon-aqueous solution or as a dried form to be used in conjunction with asuitable vehicle such as sterile, pyrogen-free water (WFI).

Parenteral formulations may include implants derived from degradablepolymers such as polyesters (i.e. polylactic acid, polylactide,polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate),polyorthoesters and polyanhydrides. These formulations may beadministered via surgical incision into the subcutaneous tissue,muscular tissue or directly into specific organs.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of Formula (I) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation of co-solvents and/orsolubility-enhancing agents such as surfactants, micelle structures andcyclodextrins.

4. Inhalation & Intranasal Administration

The compounds of the invention can be administered intranasally or byinhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler, as an aerosol spray froma pressurised container, pump, spray, atomiser (preferably an atomiserusing electrohydrodynamics to produce a fine mist), or nebuliser, withor without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or asnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation, or spray drying.

Capsules (made, for example, from gelatin orhydroxypropylmethylcellulose), blisters and cartridges for use in aninhaler or insufflator may be formulated to contain a powder mix of thecompound of the invention, a suitable powder base such as lactose orstarch and a performance modifier such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate, preferably the latter. Other suitable excipients includedextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose andtrehalose.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example, PGLA. Modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release.

5. Transdermal Administration

Suitable formulations for transdermal application include atherapeutically effective amount of a compound of the invention withcarrier. Advantageous carriers include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host.Characteristically, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound of the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

Combination Therapy

A compound of formula (I), or a pharmaceutically acceptable saltthereof, may be usefully combined with another pharmacologically activecompound, or with two or more other pharmacologically active compounds,for use in therapy. For example, a compound of the formula (I), or apharmaceutically acceptable salt thereof, as defined above, may beadministered simultaneously, sequentially or separately in combinationwith one or more agents for the treatment of disorders previouslylisted.

Therapeutic agents which are suitable for such a combination include,for example, antidiabetic agents such as metformin, sulphonylureas (e.g.glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide,thiazolidinediones (e.g. rosiglitazone, pioglitazone),PPAR-gamma-agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alphamodulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose,voglibose), DPPIV inhibitors (e.g. LAF237, MK-431), alpha2-antagonists,insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g.exendin-4) or amylin. The list also includes inhibitors of proteintyrosinephosphatase 1, substances that affect deregulated glucoseproduction in the liver, such as e.g. inhibitors ofglucose-6-phosphatase, orfructose-1,6-bisphosphatase, glycogenphosphorylase, glucagon receptor antagonists and inhibitors ofphosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvatedehydrokinase, lipid lowering agents such as for exampleHMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates(e.g. bezafibrate, fenofibrate), nicotinic acid and the derivativesthereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g.avasimibe) or cholesterol absorption inhibitors such as, for example,ezetimibe, bile acid-binding substances such as, for example,cholestyramine, inhibitors of ileac bile acid transport, HDL-raisingcompounds such as CETP inhibitors or ABC1 regulators or activesubstances for treating obesity, such as sibutramine ortetrahydrolipostatin, dexfenfluramine, axokine, antagonists of thecannabinoidi receptor, MCH-1 receptor antagonists, MC4 receptoragonists, NPY5 or NPY2 antagonists or β3-agonists such as SB-418790 orAD-9677 and agonists of the 5HT2c receptor.

Moreover, combinations with drugs for influencing high blood pressure,chronic heart failure or atherosclerosis such as e.g. A-II antagonistsor ACE inhibitors, ECE inhibitors, diuretics, β-blockers,Ca-antagonists, centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Examples of angiotensin II receptor antagonists arecandesartan cilexetil, potassium losartan, eprosartan mesylate,valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312,olmesartan, medoxomil, tasosartan, KT-3-671, GA-01 13, RU-64276,EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists arepreferably used for the treatment or prevention of high blood pressureand complications of diabetes, often combined with a diuretic such ashydrochlorothiazide.

A combination with uric acid synthesis inhibitors or uricosurics issuitable for the treatment or prevention of gout.

A combination with GABA-receptor antagonists, Na-channel blockers,topiramat, protein-kinase C inhibitors, advanced glycation end productinhibitors or aldose reductase inhibitors may be used for the treatmentor prevention of complications of diabetes. Such combinations may offersignificant advantages, including synergistic activity, in therapy.

The present invention thus provides:

The use of an agent selected from the group consisting of insulin,insulin derivative or mimetic; insulin secretagogue; insulinotropicsulfonylurea receptor ligand; PPAR ligand; insulin sensitizer;biguanide; alpha-glucosidase inhibitors; GLP-1, GLP-1 analog or mimetic;DPPIV inhibitor; HMG-CoA reductase inhibitor; squalene synthaseinhibitor; FXR or LXR ligand; cholestyramine; fibrates; nicotinic acid,and aspirin in the manufacture of a medicament for the treatment of adisease or condition in a subject mediated by the sodium D-glucoseco-transporter, wherein the agent is administered in combination with acompound according to Formula (I), or a pharmaceutically acceptable saltthereof.

The use of a compound according to Formula (I), or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for thetreatment of a disease or condition in a subject mediated by the sodiumD-glucose co-transporter, wherein the compound is administered incombination with an agent selected from the group consisting of insulin,insulin derivative, insulin mimetic; insulin secretagogue;insulinotropic sulfonylurea receptor ligand; PPAR ligand; insulinsensitizer; biguanide; alpha-glucosidase inhibitors; GLP-1, GLP-1analog, GLP-1 mimetic; DPPIV inhibitor; HMG-CoA reductase inhibitor;squalene synthase inhibitor; FXR ligand, LXR ligand; cholestyramine;fibrates; nicotinic acid, and aspirin.

The use of a compound according to formula (I), or a pharmaceuticallyacceptable salt thereof, in combination with an agent selected from thegroup consisting of insulin, insulin derivative, insulin mimetic;insulin secretagogue; insulinotropic sulfonylurea receptor ligand; PPARligand; insulin sensitizer; biguanide; alpha-glucosidase inhibitors;GLP-1, GLP-1 analog, GLP-1 mimetic; DPPIV inhibitor; HMG-CoA reductaseinhibitor; squalene synthase inhibitor; FXR ligand, LXR ligand;cholestyramine; fibrates; nicotinic acid, and aspirin.

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(I) in combination with a therapeutically effective amount of insulin,insulin derivative, insulin mimetic; insulin secretagogue;insulinotropic sulfonylurea receptor ligand; PPAR ligand; insulinsensitizer; biguanide; alpha-glucosidase inhibitors; GLP-1, GLP-1analog, GLP-1 mimetic; DPPIV inhibitor; HMG-CoA reductase inhibitor;squalene synthase inhibitor; FXR ligand, LXR ligand; cholestyramine;fibrates; nicotinic acid, and aspirin for simultaneous, separate orsequential use in therapy.

Pharmaceutical compositions may contain a therapeutically effectiveamount of a compound of the invention as defined above, either alone orin a combination with another therapeutic agent, e.g., each at aneffective therapeutic dose as reported in the art. Such therapeuticagents include:

-   a) antidiabetic agents, such as insulin, insulin derivatives and    mimetics; insulin secretagogues such as the sulfonylureas, e.g.,    Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea    receptor ligands such as meglitinides, e.g., nateglinide and    repaglinide; protein tyrosine phosphatase-1B (PTP-1B) inhibitors    such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such    as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445;    RXR ligands such as GW-0791 and AGN-194204; sodium-dependent glucose    cotransporter inhibitors such as T-1095; glycogen phosphorylase A    inhibitors such as BAY R3401; biguanides such as metformin;    alpha-glucosidase inhibitors such as acarbose; GLP-1 (glucagon like    peptide-1), GLP-1 analogs such as Exendin-4 and GLP-1 mimetics; and    DPPIV (dipeptidyl peptidase IV) inhibitors such as vildagliptin;-   b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme    A (HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin,    simvastatin, pravastatin, cerivastatin, mevastatin, velostatin,    fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin;    squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR    (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid    bile acid binding resins such as cholestyramine; fibrates; nicotinic    acid and other GPR109 agonists; cholesterol absorption inhibitors    such as ezetimibe; CETP inhibitors    (cholesterol-ester-transfer-protein inhibitors), and aspirin;-   c) anti-obesity agents such as orlistat, sibutramine and Cannabinoid    Receptor 1 (CB1) antagonists e.g. rimonabant; and-   d) anti-hypertensive agents, e.g., loop diuretics such as ethacrynic    acid, furosemide and torsemide; angiotensin converting enzyme (ACE)    inhibitors such as benazepril, captopril, enalapril, fosinopril,    lisinopril, moexipril, perinodopril, quinapril, ramipril and    trandolapril; inhibitors of the Na-K-ATPase membrane pump such as    digoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors    such as omapatrilat, sampatrilat and fasidotril; angiotensin II    antagonists such as candesartan, eprosartan, irbesartan, losartan,    telmisartan and valsartan, in particular valsartan; renin inhibitors    such as ditekiren, zankiren, terlakiren, aliskiren, RO 66-1132 and    RO-66-1168; β-adrenergic receptor blockers such as acebutolol,    atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol,    sotalol and timolol; inotropic agents such as digoxin, dobutamine    and milrinone; calcium channel blockers such as amlodipine,    bepridil, diltiazem, felodipine, nicardipine, nimodipine,    nifedipine, nisoldipine and verapamil; aldosterone receptor    antagonists; and aldosterone synthase inhibitors.-   e) agonists of peroxisome proliferator-activator receptors, such as    fenofibrate, pioglitazone, rosiglitazone, tesaglitazar, BMS-298585,    L-796449, the compounds specifically described in the patent    application WO 2004/103995 i.e. compounds of examples 1 to 35 or    compounds specifically listed in claim 21, or the compounds    specifically described in the patent application WO 03/043985 i.e.    compounds of examples 1 to 7 or compounds specifically listed in    claim 19 and especially    (R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic    or a salt thereof.

Thus, the present invention provides a pharmaceutical combinationcomprising:

-   -   i) a compound according of Formula (I), or a pharmaceutically        acceptable salt thereof,    -   ii) at least one compound selected from    -   a) antidiabetic agents,    -   b) hypolipidemic agents,    -   c) anti-obesity agents,    -   d) anti-hypertensive agents,    -   e) agonists of peroxisome proliferator-activator receptors.        Biological Assays

The inhibitory effect on the sodium-dependent glucose co-transporterSGLT (SGLT1 and SGLT2), of compounds of formula I may be demonstratedusing the following test procedures.

The ability of the substances to inhibit the SGLT-2 activity may bedemonstrated in a test set-up in which a CHO-K1 cell line (ATCC No. CCL6 1) or alternatively an HEK293 cell line (ATCC No. CRL-1573) is stablytransfected with an expression vector pZeoSV (Invitrogen, EMBL accessionnumber L36849) which contains the cDNA for the coding sequence of thehuman sodium glucose co-transporter 2 (Genbank Ace. No. NM_(—)003041)(CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport ¹⁴C-labelledalpha-methyl-glucopyranoside (¹⁴C-AMG, Amersham) into the interior ofthe cell in sodium-dependent manner.

The SGLT-2 assay is carried out as follows: CHO-hSGLT2 cells arecultivated in Ham's F12 Medium (BioWhittaker) with 10% foetal calf serumand 250 μg/mL zeocin (Invitrogen), and HEK293-hSGLT2 cells arecultivated in DMEM medium with 10% foetal calf serum and 250 μg/mLzeocin (Invitrogen). The cells are detached from the culture flasks bywashing twice with PBS and subsequently treating with trypsin/EDTA.After the addition of cell culture medium the cells are centrifuged,resuspended in culture medium and counted in a Casy cell counter. Then40,000 cells per well are seeded into a white, 96-well plate coated withpoly-D-lysine and incubated overnight at 37° C., 5% CO₂. The cells arewashed twice with 250 μl of assay buffer (Hanks Balanced Salt Solution,137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl2, 1.2 mM MgSO4 and 10 mM HEPES (pH7.4), 50 μg/mL of gentamycin). 250 μl of assay buffer and 5 μl of testcompound are then added to each well and the plate is incubated for afurther 15 minutes in the incubator. 5 μl of 10% DMSO are used as thenegative control. The reaction is started by adding 5 μl of 14 C— AMG(0.05 μCi) to each well. After 2 hours' incubation at 37° C., 5% CO₂,the cells are washed again with 250 μl of PBS (200 C) and then lysed bythe addition of 25 μl of 0.1 N NaOH (5 min. at 37° C.). 200 μl ofMicroScint20 (Packard) are added to each well and incubation iscontinued for a further 20 min at 37° C. After this incubation theradioactivity of the ¹⁴C-AMG absorbed is measured in a Topcount(Packard) using a ¹⁴C scintillation program.

To determine the selectivity with respect to human SGLT1 an analogoustest is set up in which the cDNA for hSGLTI (Genbank Ace. No. NM000343)instead of hSGLT2 cDNA is expressed in CHO-K1 or HEK293 cells.

The compounds according to the invention may for example have EC₅₀values below 1000 nM, particularly below 100 nM, most preferably below10 nM for SGLT2. The following compounds of the Examples were evaluatedin the above described assays and the results of which are collated inTable 1.

TABLE 1 Example Number SGLT2 IC₅₀ nM (n = 1-4) SGLT1 IC₅₀ nM (n = 1-4) 10.29 0.55 1-1 0.36 No data 2 9.2 97 2-1 1.45 195

It can be seen that the compounds of the invention are useful asinhibitors of SGLT and therefore useful in the treatment of diseases andconditions mediated by SGLT such as the metabolic disorders disclosedherein.

Method of Preparation

The invention provides, in another aspect, a process for preparing acompound of Formula (I). The schemes, outlined below, show generalroutes for synthesizing compounds of Formula (I). In the reactionsdescribed in the schemes herein below, any reactive group present, suchas hydroxyl, amino, carbonyl or imino groups may be protected during thereaction by conventional protecting groups such as trimethylsilyl,tert-butyldimethylsilyl, benzyl, acetal, ketal etc., which are cleavedagain after the reaction. Unless otherwise stated in the reactionschemes below, the variables have the meaning as defined hereinabove.

Compounds of formula (II), wherein Lg is a leaving group such as halogenmay be reacted with alkyl lithium or Mg to provide compounds of formula(III) wherein M is selected from Li or Mg-Halogen. Compounds of formula(III) may be reacted with compounds of formula (IV) wherein P¹ is aprotecting group such as acetonide and X¹ is halogen or carbonate, toprovide compound of formula (V) which may be reduced to providecompounds of formula (VI). The compounds of formula (VI) may berearranged to obtain compounds of formula (VII). The anomeric alcoholgroup of formula (VII) may be converted to an ester then substitutedwith a halogen by treating it with a hydrohalic acid such as HBr or HClin acetic acid to form a compound represented by Formula (IX). Thehalogen of Formula (IX) may be displaced with an alcohol to form acompound of Formula (I) wherein X is —O— or an amine to form a compoundof Formula (I) wherein X is NR⁵ (see Scheme 1).

Compounds of the invention in which X is —S— can be prepared by reactinga compound of Formula (VIII) with thiourea in the presence of trimethylsilyl triflate followed by treatment with an alkyl iodide compound inthe presence of a hindered base (see Scheme 2).

Compounds of Formula (I) wherein X is —S(O)— or —S(O)₂— can be preparedfrom a compound of formula (I) wherein in X is —S— by treating it withan oxidizing agent such as urea hydrogen peroxide (see Scheme 3).

A compound of formula (X), wherein Lg is a leaving group such ashalogen, may be reacted with alkyl lithium or Mg to provide compounds offormula (XI) wherein M is selected from Li or Mg-Halide. A compound offormula (XI) may be reacted with aldehyde of formula (XII) to provide analcohol of Formula (XIIIa) which can be reduced with a reducing agent.In one embodiment, compounds represented by Formula (IIIa) can bereduced by treatment with a trialkylsilane in the presense of BF₃ and anether. A compound of Formula (XIII) may further be converted to acompound of formula (I) by the reactions described in Schemes 1-3 (seeScheme 4).

Alternatively, a compound of formula (XI) wherein M is selected from Lior Mg-Halide may be reacted with an aldehyde of formula (XIV) followedby reduction with a reducing agent such as a trialkylsilane in thepresense of BF₃ and an ether to provide compounds of formula (I) (seeScheme 5).

A compound of formula (XV) may be converted to olefin of Formula (XVI)which may be converted to lactone of Formula (XVII) using ozonlysis ordihydroxylation followed by periodate cleavage. A compound of formula(XVII) may be converted to a compound of formula (XIII) which is furtherconverted to a compound of Formula (I) as described in Schemes 1-3 (seeScheme 6).

Intermediates

Intermediate (II) can be prepared by reacting an acid chloride (XVIII)with an aromatic compound represented by Formula (XIX) in the presenceof AlCl₃ as shown in Scheme 7.

3,4,5-Trihydroxy-2-(R)-hydroxy-pentanal may be cyclised to obtainfuranyl alcohol of formula (XX) which may be converted to intermediate(IV) using functional group transformations known in the literature.

Compounds of formula (IV) may be reacted with organometalic intermediateof formula (XXI) to provide compounds of formula (XXII) which mayfurther be reduced to obtain compounds of formula (XXIII). Compounds offormula (XXIII) on rearrangement and appropriate protection may providecompounds of formula (XXIV). Compounds of formula (XXIV) may be oxidizedto provide aldehyde of formula (XII) which may further be converted to acompound of formula (XIV) by the reactions described in Schemes 1-3 (seeScheme 9).

It will be understood that the processes detailed above and elsewhereherein are solely for the purpose of illustrating the invention andshould not be construed as limiting. A process utilizing similar oranalogous reagents and/or conditions known to one skilled in the art mayalso be used to obtain a compound of the invention.

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group”, unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such asJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press,London and New York 1973, in T. W. Greene and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, Third edition, Wiley, New York 1999, in“The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), AcademicPress, London and New York 1981, in “Methoden der organischen Chemie”(Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/I,Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit,“Aminosauren, Peptide, Proteine” (Amino acids, Peptides, Proteins),Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in JochenLehmann, “Chemie der Kohlenhydrate: Monosaccharide and Derivate”(Chemistry of Carbohydrates: Monosaccharides and Derivatives), GeorgThieme Verlag, Stuttgart 1974. A characteristic of protecting groups isthat they can be removed readily (i.e. without the occurrence ofundesired secondary reactions) for example by solvolysis, reduction,photolysis or alternatively under physiological conditions (e.g. byenzymatic cleavage).

Any mixtures of final products or intermediates obtained can beseparated on the basis of the physico-chemical differences of theconstituents, in a known manner, into the pure final products orintermediates, for example by chromatography, distillation, fractionalcrystallisation, or by the formation of a salt if appropriate orpossible under the circumstances.

The following Examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. If not mentionedotherwise, all evaporations are performed under reduced pressure. Thestructure of final products, intermediates and starting materials havebeen confirmed by standard analytical methods, e.g., microanalysis,melting point (m.p.) and spectroscopic characteristics, e.g. MS and NMR.Abbreviations used are those conventional in the art.

Intermediates Synthesis of6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]dioxine

Step I: To a stirred solution of 2-bromo-5-iodobenzoic acid (150 g, 458mmol) in dichloromethane (1500 ml) was added DMF (2.0 ml) followed byoxalylchloride (58.2 ml, 688 mmol) at 0° C. in drop wise fashion overthe period of 30 min. After complete addition, the reaction mixture wasstirred at room temperature for 3 h. Volatiles were evaporated underreduced pressure to give 2-bromo-5-iodo-benzoyl chloride (−158 g). Thecrude product was used for the next step immediately. (Note: The productshould not be exposed to air).

Step II: To a stirred solution of 2-bromo-5-iodo-benzoyl chloride (−158g, 457 mmol) in DCM (1500 ml) was added benzo(1,4)-dioxane (65.8 ml, 549mmol) at 0° C. To this reaction mixture, aluminum chloride (195.4 g,1465 mmol) was added in portions. After stirring for overnight at roomtemperature, reaction mixture was poured into crushed ice. This wasextracted with dichloromethane (1000 ml×2). Dichloromethane layer waswashed with water (1000 ml), saturated aqueous sodium bicarbonatesolution (1000 ml×2), brine (1000 ml), dried over sodium sulfate, andconcentrated. The solid product was triturated with hexanes. The productwas dried under vacuum to give 180 g of(2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone.

¹H NMR (400 MHz, DMSO-D₆): δ 4.29-4.37 (m, 4H), 7.02 (d, J=8.4 Hz, 1H),7.16 (d, J=2.4 Hz, 1H), 7.18-7.19 (m, 1H), 7.53 (d, J=8.4 Hz, 1H),7.77-7.81 (m, 1H), 7.82 (d, J=2.0 Hz, 1H).

Step III: (Note: This reaction was done in 5 lit. R. B. flask). To astirred solution of(2-bromo-5-iodo-phenyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone(180 g, 404.49 mmol) in trifluoroacetic acid (600 ml) was addedtriethylsilane (386.5 ml, 2426.9 mmol) followed by triflic acid (2.3 ml)at room temperature (note: after addition of 1 drop of triflic acidexotherm was observed so addition was done very slowly in such a waythat reaction mixture refluxed gently). After stirring for 25 min atroom temperature, volatiles were evaporated under reduced pressure. Theresulting residue was taken in ethyl acetate (1500 ml) and washed withsaturated aqueous sodium bicarbonate solution (1000 ml×2), water (1000ml), brine (1000 ml), dried over sodium sulfate, and concentrated. Theresulting residue was triturated with hexane. The residue wasrecrystallized from ethanol to give 147 g of6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]dioxine.

¹H NMR (400 MHz, DMSO-D₆): δ 3.90 (s, 4H), 4.2 (s, 2H), 6.65 (dd, J=8.4Hz, J=2.0 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 7.39(d, J=8.4 Hz, 1H), 7.50 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.67 (d, J=2.8 Hz,1H).

EXAMPLES Example 1 Synthesis of(2S,3R,4R,5S)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol

Step-I: To a stirred solution of L-(−)-xylose (60 g, 400 mmol) inacetone (600 ml) was added anhydrous magnesium sulfate (96.2 g, 800mmol) under argon bubbling. Then to it was added concentrated sulfuricacid (5.96 ml, 112 mmol). After stirring for overnight at roomtemperature, reaction mixture was filtered. The solid was washed withacetone. The filtrate was basified (pH=8.7) by ammonium hydroxidesolution. After 10 min. suspended solid was filtered, the filtrate wasconcentrated to give 78 g of(3aS,3bR,7aS,8aS)-2,2,5,5-tetramethyl-tetrahydro-[1,3]dioxolo[4,5]furo[3,2-d][1,3]dioxineas a yellow oil. ¹H NMR (400 MHz, CD₃OD): δ 1.29 (s, 6H), 1.43 (s, 3H),1.44 (s, 3H), 3.92 (d, J=13.6 Hz, 1H), 3.98 (q, J=1.6 Hz, 1H), 4.13-4.18(m, 1H), 4.31 (d, J=2.4 Hz, 1H), 4.48 (d, J=2.4 Hz, 1H), 5.89 (d, J=3.2Hz, 1H).

Step-II: To a stirred solution of(3aS,3bR,7aS,8aS)-2,2,5,5-tetramethyl-tetrahydro-[1,3]dioxolo[4,5]furo[3,2-d][1,3]dioxine(78 g) in water (250 ml) was added 0.1N HCl (20 ml) at ambienttemperature. After stirring for 6 h, reaction was neutralized by theaddition of 50% w/w aqueous K₂HPO₄ (until pH=7). The solvent wasevaporated under reduced pressure, ethyl acetate was added. The solidprecipitated was filtered, the filtrate was concentrated to give 45 g of(3aS,5S,6R,6aS)-5-hydroxymethyl-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-olas an orange oil. ¹H NMR (400 MHz, CD₃OD): δ 1.29 (s, 3H), 1.44 (s, 3H),3.73 (dd, J=6.4, 11.6 Hz, 1H), 3.79 (dd, J=6.0, 11.6 Hz, 1H), 4.08-4.17(m, 2H), 4.45 (d, J=4.0 Hz, 1H), 5.87 (d, J=4.0 Hz, 1H).

Step-III: To a stirred solution of(3aS,5S,6R,6aS)-5-hydroxymethyl-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-ol(30 g, 157 mmol) in acetone (450 ml) and water (150 ml) was added sodiumbicarbonate (39.8 g, 473 mmol), sodium bromide (3.25 g, 31 mmol) andTEMPO (490 mg, 3.1 mmol) at 20° C. The mixture was cooled to 0-5° C. andsolid trichloroisocyanuric acid (TCCA, 36.69 g, 157 mmol) was then addedin portions. After stirring for 24 h at room temperature, methanol (25ml) was added stirred for additional 1 h. The white suspension wasformed. This was filtered, washed with acetone (50 ml×2). The volatileswere evaporated under reduced pressure. The aqueous layer was extractedwith ethyl acetate (300 ml×3) and combined organic layers wereconcentrated to thick oily mixture with some solid residue. This wastaken in acetone and filtered. The filtrate was concentrated to give 25g of(3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxole-5-carboxylicacid as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ 1.30 (s, 3H), 1.44(s, 3H), 4.35 (d, J=2.8 Hz, 1H), 4.50 (d, J=2.0 Hz, 1H), 4.69 (d, J=3.6Hz, 1H), 5.97 (d, J=3.2 Hz, 1H).

Step-IV: To a stirred solution of(3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxole-5-carboxylicacid (20 g, 98 mmol) in THF (400 ml) was added TBTU (47.2 g, 147 mmol),N-methylmorpholine (NMM, 16.16 ml, 147 mmol) at room temperature andstirred for 30 min. To it was added morpholine (12.99 ml, 147 mmol) andstirred for 6 h. The solid was filtered off by filtration and it waswashed with THF. The filtrate was concentrated and resulting residue waspurified by silica gel column chromatography to give 17.8 g of((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-morpholin-4-yl-methanoneas a white solid. ¹H NMR (400 MHz, CD₃OD): δ 1.33 (s, 3H), 1.49 (s, 3H),3.42-3.53 (m, 2H), 3.62-3.83 (m, 6H), 4.47 (d, J=2.0 Hz, 1H), 4.57 (d,J=3.6 Hz, 1H), 4.59 (d, J=2.0 Hz, 1H), 6.00 (d, J=3.2 Hz, 1H).

Step-V: To a cooled solution of((3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-morpholin-4-yl-methanone(11.05 g, 256 mmol) in THF (200 ml) was added 2.0 M solution ofisopropylmagnesium chloride (12.78 ml, 256 mmol) under stirring at 0° C.and stirred for additional 1.5 h. To this was added a solution of6-(2-bromo-5-iodo-benzyl)-2,3-dihydro-benzo[1,4]dioxine (4.0 g, 146mmol) in THF (50 ml) at 0° C. and then stirred at room temperature for 2h. The reaction mixture was quenched by the addition of aqueoussaturated ammonium chloride solution and extracted with ethyl acetate(200 ml×3). Combined organic layers were washed with brine (500 ml),dried over sodium sulfate, concentrated and purified by silica gelcolumn chromatography to give 4.7 g of[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-methanone.¹H NMR (400 MHz, CDCl₃): δ 1.35 (s, 3H), 1.53 (s, 3H), 2.92 (d, J=4.0Hz, 1H), 4.04 (d, J=3.6 Hz, 2H), 4.23 (s, 4H), 4.54 (br s, 1H), 4.56 (d,J=3.6 Hz, 1H), 5.21 (d, J=2.8 Hz, 1H), 6.05 (d, J=3.2 Hz, 1H), 6.67 (s,2H), 6.79 (d, J=9.2 Hz, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.75-7.77 (m, 2H).MS (ES) m/z 490.7 (M+1).

Step-VI: To a stirred solution of[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-((3aS,5R,6S,6a5)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-methanone(4.7 g, 9.6 mmol) in methanol (80 ml) was added CeCl₃.7H₂O (4.27 g, 11.5mmol) at room temperature and stirred till the solid got dissolved. Thenthe reaction mixture was cooled to −78° C. and sodium borohydride (434mg, 11.5 mmol) was added in portions. After stirring for 1 h at sametemperature reaction mixture was warmed up to 0° C. and quenched by theaddition of saturated ammonium chloride solution. Volatiles wereevaporated under reduced pressure. The aqueous layer was extracted withethyl acetate and combined organic layers were concentrated underreduced pressure to give 5.0 g of(3aS,5S,6R,6aS)-5-{(R)-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-hydroxy-methyl}-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-ol.The crude product was taken for the next step. MS (ES) m/z 511.8 (M+18).

A solution of(3aS,5S,6R,6aS)-5-{(R)-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-hydroxy-methyl}-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-ol(5.0 g, 10.1 mmol) in acetic acid (30 ml) and water (22 ml) was heatedto 100° C. for 15 h. Reaction mixture was concentrated under reducedpressure to give 4.7 g of crude product(3S,4R,5R,6S)-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2,3,4,5-tetraol.This was used as such for next step. MS (ES) m/z 470.0 (M+18).

To a cooled solution of(3S,4R,5R,6S)-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2,3,4,5-tetraol(4.7 g, 9.9 mmol) in pyridine (20 ml) was added acetic anhydride (8.1 g,79.5 mmol) at 0° C. After complete addition reaction mixture was stirredat room temperature for 2 h. Pyridine was evaporated under reducedpressure. The resulting residue was taken in ethyl acetate and washedwith aqueous 1 N sodium bisulfate solution followed by brine, dried oversodium sulfate, concentrated to give 3.5 g of acetic acid(3S,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylester.

Step-IX: To a stirred solution of acetic acid(3S,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylester (2.75 g, 4.4 mmol) in toluene (25 ml) was addedtricyclohexylphosphine (495 mg, 1.8 mmol), a solution of potassiumphosphate tribasic (3.75 g, 1.8 mmol) in water (5 ml),cyclopropylboronic acid (1.14 g, 13.2 mmol). The reaction mixture wasdegassed for 45 min then added palladium (II) acetate (148 mg, 0.7mmol). Reaction mixture was stirred at 90° C. for overnight. Reactionmixture was cooled to room temperature and was filtered through celitebed, washed with ethyl acetate (25 ml). Organic layer was washed withwater (25 ml) followed by brine (25 ml), dried over sodium sulfate,concentrated and purified by column chromatography to give 1.9 g ofacetic acid(3S,4R,5S,6S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylester. MS (ES) m/z 600.3 (M+18).

Step-X: To a stirred solution of acetic acid(3S,4R,5S,6S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylester (1.9 g, 3.3 mmol) in dioxane (8 ml) was added thiourea followed bytrimethylsilyl trifluoromethane sulfonate (0.88 ml, 4.8 mmol). Thereaction mixture was heated to 80° C. for 3 h. Reaction mixture wascooled to room temperature and added methyl iodide (0.52 ml, 8.1 mmol)followed by diisopropylethyl amine (2.79 ml, 16.2 mmol) and stirred foradditional 3 h. Reaction mixture was diluted with ethyl acetate (40 ml)and washed with water (40 ml). The organic layer was concentrated. Theresulting residue was taken in methanol (10 ml) and heated to 60° C. for2 h, then cooled to 0° C. and stirred for additional 1 h. The resultingsolid was filtered and washed with methanol to give 750 mg of aceticacid(3S,4R,5S,6S)-4,5-diacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-2-methylsulfanyl-tetrahydro-pyran-3-ylester. ¹H NMR (400 MHz, DMSO-d₆): δ 0.55-0.59 (m, 2H), 0.85 (d, J=8.8Hz, 2H), 1.70 (s, 3H), 1.82-1.89 (m, 1H), 1.93 (s, 3H), 2.03 (s, 3H),2.08 (s, 3H), 3.95 (d, J=15.2 Hz, 1H), 4.02 (d, J=16.8 Hz, 1H), 4.00 (s,4H), 4.65 (d, J=10.0 Hz, 1H), 4.87 (d, J=10.0 Hz, 1H), 5.03-5.12 (m,2H), 5.34 (t, J=10.0 Hz, 1H), 6.58-6.60 (m, 2H), 6.73 (d, J=7.6 Hz, 1H),6.91 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H).MS (ES) m/z 588.3 (M+18).

Step-XI: To a stirred solution of acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-2-methylsulfanyl-tetrahydro-pyran-3-ylester (80 mg, 0.14 mmol) in methanol:THF:water (3:2:1 mixture, 6 ml) wasadded lithium hydroxide (9 mg, 0.4 mmol). After stirring for 2 h at roomtemperature, volatiles were evaporated under reduced pressure. Theresulting residue was taken in ethyl acetate (10 ml) and washed withbrine (5 ml), brine containing 1 ml of 5% aqueous KHSO₄ (5 ml), brine (5ml), dried over sodium sulfate, concentrated and purified by preparativeHPLC to furnish 55 mg of(2S,3R,4R,5S)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol.¹H NMR (400 MHz, CD₃OD): δ 0.52-0.60 (m, 2H), 0.80-0.90 (m, 2H),1.78-1.88 (m, 1H), 2.15 (s, 3H), 3.32-3.35 (m, 3H), 4.05 (q, J=15.2 Hz,2H), 4.11 (d, J=8.8 Hz, 1H), 4.17 (s, 4H), 4.38 (d, J=10 Hz, 1H), 6.61(d, J=8.0 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 7.15(d, J=7.6 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H). MS (ES) m/z 462.3 (M+18).

Following examples were prepared by using the procedures described forExample 1 and the appropriate starting materials.

Ex. No. Structure/IUPAC name Spectral data 1-1

¹H NMR (400 MHz, CD₃OD): δ 1.08 (t, J = 7.6 Hz, 3H), 2.13 (s, 3H), 2.59(q, J = 7.6 Hz, 2H), 3.32- 3.50 (m, 3H), 3.89 (s, 2H), 4.12 (d, J = 9.2Hz, 1H), 4.17 (s, 4H), 4.38 (d, J = 9.6 Hz, 1H), 6.57 (d, J = 9.6 Hz,2H), 6.68 (d, J = 8.0 Hz, 1H), 7.12-7.22 (m, 3H). MS (ES) m/z 450.2 (M +18). 1-2

¹H NMR (400 MHz, CD₃OD): δ 1.08 (t, J = 7.8 Hz, 3H), 1.92-1.96 (m, J =5.6 Hz, 2H), 2.13 (s, 3H), 2.6 (q, J = 7.8 Hz, 2H), 2.70 (t, J = 6.4 Hz,2H), 3.34-3.47 (m, 3H), 3.90 (s, 2H), 4.08-4.13 (m, 3H), 4.38 (d, J =9.6 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 6.78-6.81 (m, 2H), 7.13-7.21 (m,3H). MS (ES) m/z 448.3 (M + 18). 1-3

¹H NMR (400 MHz, CD₃OD): δ 2.12 (s, 3H), 3.30-3.44 (m, 3H), 3.96- 4.02(m, 2H), 4.12 (d, J = 9.8 Hz, 1H), 4.18 (s, 4H), 4.38 (d, J = 9.3 Hz,1H), 6.68 (s, 2H), 6.71 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H),7.24 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H). MS (ES) m/z 501 (M + 18). 1-4

¹H NMR (400 MHz, CDCl₃): δ 0.52- 0.68 (m, 2H), 0.80-0.95 (m, 2H),1.78-1.90 (m, 1H), 1.92-2.12 (m, 3H), 2.18 (s, 3H), 2.71 (t, J = 5.6 Hz,2H), 3.56 (t, J = 8.8 Hz, 2H), 3.70 (t, J = 8.8 Hz, 1H), 4.07 (q, J =15.6 Hz, 2H), 4.12-4.22 (m, 2H), 4.38 (d, J = 9.2 Hz, 1H), 6.69 (d, J =7.4 Hz, 1H), 6.80 (s, 1H), 6.85 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 7.6Hz, 1H), 7.10 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H). MS (ES) m/z 460.2 (M+18). 1-5

¹H NMR (400 MHz, CDCl₃): δ 1.95- 2.02 (m, 2H), 2.17 (s, 3H), 2.73 (t, J= 6.4 Hz, 2H), 3.46-3.60 (m, 2H), 3.67 (t, J = 8.8 Hz, 1H), 3.99 (q, J =16 Hz, 2H), 4.10-4.22 (m, 3H), 4.37 (d, J = 9.6 Hz, 1H), 6.70 (d, J =8.4 Hz, 1H), 6.85 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 7.10-7.20 (m, 2H),7.56 (d, J = 8.0 Hz, 1H). MS (ES) m/z 499 (M + 18). 1-6

¹H NMR (400 MHz, CD3OD): δ 2.12 (s, 3H), 2.75-2.85 (m, 2H), 3.20-3.55(m, 3H), 3.93 (t, J = 5.2 Hz, 2H), 4.05 (s, 2H), 4.12 (d, J = 9.2 Hz,1H), 4.38 (d, J = 9.2 Hz, 1H), 4.68 (s, 2H), 6.38 (s, 1H), 6.95-7.08 (m,2H), 7.17 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H).MS (ES) m/z 500.1 (M + 18). 1-7

¹H NMR (400 MHz, CD₃OD): δ 1.08 (t, J = 7.2 Hz, 3H), 2.13 (s, 3H), 2.59(q, J = 7.6 Hz, 2H), 2.75- 2.82 (m, 2H), 3.30-3.50 (m, 3H), 3.92 (t, J =6.0 Hz, 2H), 3.97 (s, 2H), 4.12 (d, J = 8.8 Hz, 1H), 4.38 (d, J = 9.2Hz, 1H), 4.65 (s, 2H), 6.77 (s, 1H), 6.94 (d, J = 7.6 Hz, 1H), 7.00 (d,J = 8.0 Hz, 1H), 7.12- 7.26 (m, 3H). MS (ES) m/z 448.2 (M + 18).

Example 2 Synthesis of(2S,3R,4R,5S)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol

Step-I: A mixture of urea hydrogen peroxide (297 mg, 3.1 mmol) andphthalic anhydride (233 mg, 1.5 mmol) were taken in acetonitrile (3 ml)and stirred until the solids were dissolved. To this was added asolution of acetic acid(2R,3S,4R,5S,6S)-4,5-diacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-2-methylsulfanyl-tetrahydro-pyran-3-ylester (300 mg, 0.5 mmol) in acetonitrile (2 ml) and stirred at ambienttemperature for 7 h. Reaction mixture was diluted with ethyl acetate (10ml), washed with saturated sodium bicarbonate (10 ml), water (10 ml),dried over sodium sulfate, concentrated to give 310 mg of acetic acid(2R,3S,4R,5S,6S)-4,5-diacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-2-methanesulfonyl-tetrahydro-pyran-3-ylester as a white solid. MS (ES) m/z 620.2 (M+18).

To a stirred solution of acetic acid(2R,3S,4R,5S,6S)-4,5-diacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-2-methanesulfonyl-tetrahydro-pyran-3-yl(350 mg, 0.58 mmol) in methanol:THF:water (3:2:1 mixture, 12 ml) wasadded lithium hydroxide (36 mg, 0.9 mmol). After stirring for 2 h atroom temperature, volatiles were evaporated under reduced pressure. Theresulting residue was taken in ethyl acetate (10 ml) and washed withbrine (5 ml), brine containing 1 ml of 5% aqueous KHSO₄ (5 ml), brine (5ml), dried over sodium sulfate, concentrated and purified by preparativeHPLC to furnish 240 mg of(2S,3R,4R,5S)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol.¹H NMR (400 MHz, CD₃OD): δ 0.52-0.62 (m, 2H), 0.82-0.91 (m, 2H),1.80-1.90 (m, 1H), 2.92 (s, 3H), 3.40 (t, J=9.6 Hz, 1H), 3.55 (t, J=8.8Hz, 1H), 3.88 (t, J=9.2 Hz, 1H), 4.05 (s, 2H), 4.17 (s, 4H), 4.27 (d,J=9.2 Hz, 1H), 4.52 (d, J=9.6 Hz, 1H), 6.60 (dd, J=8.0, 2.4 Hz, 2H),6.69 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H),7.18 (dd, J=8.0, 1.6 Hz, 1H).

MS (ES) m/z 494.2 (M+18).

Following examples were prepared by using the procedures described forExample 2 and the appropriate starting materials.

Ex. No. Structure/IUPAC name Spectral data 2-1

¹H NMR (400 MHz, CD₃OD): δ 1.09 (t, J = 8.8 Hz, 3H), 2.60 (q, J = 7.4Hz, 2H), 2.92 (s, 3H), 3.42 (t, J = 9.3 Hz, 1H), 3.55 (t, J = 8.8 Hz,1H), 3.87-3.91 (m, 3H), 4.20 (s, 4H), 4.26 (d, J = 10 Hz, 1H), 4.53 (d,J = 9.6 Hz, 1H), 6.55-6.58 (m, 2H), 6.72 (d, J = 8.0 Hz, 1H), 7.14 (s,1H), 7.17-7.24 (m, 2H). MS (ES) m/z 482.3 (M + 18). 2-2

¹H NMR (400 MHz, CD₃OD): δ 1.09 (t, J = 7.8 Hz, 3H), 1.92-195 (m, 2H),2.63 (q, J = 7.3 Hz, 2H), 2.69 (t, J = 6.4 Hz, 2H), 2.92 (s, 3H), 3.41(t, J = 9.8 Hz, 1H), 3.55 (t, J = 9.3 Hz, 1H), 3.86 3.90 (m, 3H), 4.10(t, J = 9.8 Hz, 2H), 4.27 (d, J = 9.8 Hz, 1H), 4.52 (d, J = 9.8 Hz, 1H),6.58 (d, J = 7.8 Hz, 1H), 6.78-6.80 (m, 2H), 7.14 (s, 1H), 7.17-7.23 (m,2H). MS (ES) m/z 480.3 (M + 18). 2-3

¹H NMR (400 MHz, CD₃OD): δ 2.92 (s, 3H), 3.31-3.35 (m, 1H), 3.56 (t, J =9.6 Hz, 1H), 3.90 (t, J = 9.2 Hz, 1H), 3.98 (s, 2H), 4.19 (s, 4H), 4.28(d, J = 9.6 Hz, 1H), 4.52 (d, J = 9.6 Hz, 1H), 6.63-6.65 (m, 2H), 6.72(d, J = 8.3 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.56 (d, J= 8.3 Hz, 1H). MS (ES) m/z 534.2 (M + 18). 2-4

¹H NMR (400 MHz, CDCl₃): δ 0.58- 0.70 (m, 2H), 0.85-0.95 (m, 2H),1.80-1.92 (m, 1H), 1.92-2.2 (m, 2H), 2.72 (t, J = 5.6 Hz, 2H), 2.89 (s,3H), 3.59 (t, J = 8.8 Hz, 1H), 3.79 (t, J = 8.8 Hz, 1H), 4.0-4.12 (m,3H), 4.15 (t, J = 5.6 Hz, 2H), 4.27 (d, J = 9.6 Hz, 1H), 4.38 (d, J =10.0 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.78-6.88 (m, 2H), 6.98-7.08 (m,2H), 7.16 (d, J = 7.6 Hz, 1H). MS (ES) m/z 492.3 (M + 18). 2-5

¹H NMR (400 MHz, CD3OD): δ 1.90-2.02 (m, 2H), 2.71 (t, J = 6 Hz, 2H),2.90 (s, 3H), 3.20-3.40 (m, 1H), 3.54 (t, J = 8.8 Hz, 1H), 3.87 (t, J =9.2 Hz, 1H), 3.98 (s, 2H), 4.11 (t, J = 4.8 Hz, 2H), 4.28 (d, J = 9.6Hz, 1H), 4.52 (d, J = 9.6 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.86 (d, J= 7.6 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.22 (s, 1H), 7.55 (d, J = 8.4Hz, 1H). MS (ES) m/z 530.2 (M + 18).

Example 3 Synthesis of(2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol

Step-I: Acetic acid(3S,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylester (3.5 g) was taken in 33% HBr in acetic acid (10 ml) and stirredfor 1 h at room temperature. To this was added dichloromethane (20 ml)and stirred for additional 30 min. This was diluted with dichloromethane(50 ml), poured into crushed ice and neutralized with sodiumbicarbonate. Organic layer was separated, extracted with DCM (50 ml×2),combined organic layers were washed with water (200 ml×2), brine (200ml), dried over sodium sulfate, concentrated to give 3.0 g of aceticacid(3S,4R,5S,6S)-4,5-diacetoxy-2-bromo-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-3-ylester.

Step-II: To a stirred solution of acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-2-bromo-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-3-ylester (2.5 g, 3.89 mmol) in methanol (38 ml) was added zinc oxide (429mg, 4.6 mmol) at room temperature. Then the reaction mixture wasrefluxed for 1.5 h. Reaction mixture was cooled to room temperature,filtered through celite bed, filtrate was concentrated and purified bycolumn chromatography to give 1.8 g of acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-2-methoxy-tetrahydro-pyran-3-ylester as a yellow solid.

Step-III: To a stirred solution of acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-2-methoxy-tetrahydro-pyran-3-ylester (700 mg, 1.18 mmol) in toluene (11 ml) was addedtricyclohexylphosphine (132 mg, 0.47 mmol), a solution of potassiumphosphate tribasic (1.0 g, 4.72 mmol) in water (1 ml), ethylboronic acid(262 mg, 3.54 mmol). The reaction mixture was degassed for 40 min thenadded palladium (II) acetate (39 mg, 0.18 mmol). Reaction mixture wasstirred at 90° C. for overnight. Reaction mixture was cooled to roomtemperature and was filtered through celite bed, washed with ethylacetate (10 ml). Organic layer was washed with water (15 ml) followed bybrine (15 ml), dried over sodium sulfate, concentrated and purified bycolumn chromatography to give 320 mg of acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-2-methoxy-tetrahydro-pyran-3-ylester as white solid.

Step-IV: To a stirred solution of acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-2-methoxy-tetrahydro-pyran-3-ylester (300 mg, 0.55 mmol) in methanol:THF:water (3:2:1 mixture, 6 ml)was added lithium hydroxide (46 mg, 1.10 mmol). After stirring for 2 hat room temperature, volatiles were evaporated under reduced pressure.The resulting residue was taken in ethyl acetate (10 ml) and washed withbrine (5 ml), brine containing 1 ml of 5% aqueous KHSO₄ (5 ml), brine (5ml), dried over sodium sulfate, concentrated and purified by preparativeHPLC to furnish 90 mg(2S,3R,4R,5S,6S)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triolas white solid. ¹H NMR (400 MHz, CD₃OD): δ 0.56-0.58 (m, 2H), 0.84-0.87(m, 2H), 1.80-1.85 (m, 1H), 3.27-3.44 (m, 3H), 3.48 (s, 3H), 4.05 (d,J=6.4 Hz, 2H), 4.10 (d, J=9.3 Hz, 1H), 4.17 (s, 4H), 4.30 (d, J=7.8 Hz,1H), 6.62 (d, J=8.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 2H), 6.98 (d, J=7.8 Hz,1H), 7.16-7.19 (m, 2H). MS (ES) m/z 446.3 (M+18).

Following examples were prepared by using the procedures described forExample 3 and the appropriate starting materials.

Ex. No. Structure/IUPAC name Spectral data 3-1

¹H NMR (400 MHz, CD₃OD): δ 1.91-1.97 (m, 2H), 2.71 (t, J = 6.4 Hz, 2H),3.25-3.30 (m, 2H), 3.38- 3.45 (m, 1H), 3.47 (s, 3H), 3.98 (d, J = 6 Hz,2H), 4.09-4.11 (m, 3H), 4.29 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 7.8 Hz,1H), 6.85-6.88 (m, 2H), 7.15 (dd, J = 8.5, 2.4 Hz, 1H), 7.23 (d, J = 1.9Hz, 1H). 7.23 (d, J = 8.3 Hz, 1H). MS (ES) m/z 483.3 (M + 18). 3-2

¹H NMR (400 MHz, CD₃OD): δ 1.08 (t, J = 6.3 Hz, 3H), 1.92-1.96 (m, 2H),2.59 (q, J = 7.4 Hz, 2H), 2.69 (t, J = 6.4 Hz, 2H), 3.28-3.47 (m, 3H),3.48 (s, 3H), 3.82-3.93 (m, 2H), 4.08-4.12 (m, 3H), 4.30 (d, J = 7.8 Hz,1H), 6.59 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 10.3 Hz, 2H), 7.15-7.22 (m,3H). MS (ES) m/z 432.4 (M + 18). 3-3

¹H NMR (400 MHz, CD₃OD): δ 0.54-0.58 (m, 2H), 0.82-0.87 (m, 2H),1.83-184 (m, 1H), 1.92-1.97 (m, 2H), 2.70 (t, J = 6.4 Hz, 2H), 3.27-3.44(m, 3H), 3.47 (s, 3H), 4.05-4.11 (m, 5H), 4.29 (d, J = 7.8 Hz, 1H), 6.59(d, J = 8.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 7.8 Hz, 1H),7.15-7.18 (m, 2H). MS (ES) m/z 444.3 (M + 18). 3-4

¹H NMR (400 MHz, CD₃OD): δ 1.08 (t, J = 6.3 Hz, 3H), 2.59 (q, J = 7.4Hz, 2H), 3.35-3.48 (m, 6H), 4.90 (d, J = 2.5 Hz, 2H), 4.11 (d, J = 9.3Hz, 1H), 4.17 (s, 4H), 4.30 (d, J = 7.8 Hz, 1H), 6.55-6.69 (m, 2H), 6.68(d, J = 8.4 Hz, 1H), 7.15-7.23 (m, 3H). MS (ES) m/z 434.4 (M + 18).

Example 4 Synthesis ofN-[(3S,4R,5R,6S)-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-3,4,5-trihydroxy-tetrahydro-pyran-2-yl]-N-propyl-acetamide

Step-I: Acetic acid(3S,4R,5S,6S)-3,4,5-triacetoxy-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-tetrahydro-pyran-2-ylester (300 mg) was taken in 33% HBr in acetic acid (1.2 ml) and stirredfor 1 h at room temperature. To this was added dichloromethane (2 ml)and stirred for additional 30 min. This was diluted with dichloromethane(5 ml), poured into crushed ice and neutralized with sodium bicarbonate.Organic layer was separated, extracted with DCM (8 ml×2), combinedorganic layers were washed with water (10 ml×2), brine (10 ml), driedover sodium sulfate, concentrated to give 250 mg of acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-2-bromo-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-tetrahydro-pyran-3-ylester.

Step-II: To a stirred solution of acetic acid(3S,4R,5S,6S)-4,5-diacetoxy-2-bromo-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-tetrahydro-pyran-3-ylester (250 mg, 0.4 mmol) in DCM (2 ml) was added propyl amine (0.4 ml)and stirred for 1.5 h at 40° C. Then it was cooled to room temperatureand added pyridine (0.3 ml, 3.39 mmol), acetic anhydride (0.3 ml, 3.39mmol), stirred for overnight. Volatiles were evaporated under reducedpressure, resulting residue was taken in DCM and was with 1N HCl (2 ml),brine, dried over sodium sulfate and concentrated to give 170 mg ofsolid. The resulting solid (170 mg, 0.3 mmol) was taken inmethanol:water:THF (1:1:3, 5 ml) mixture and added lithium hydroxidemonohydrate (24 mg, 0.6 mmol) at room temperature and stirred for 2.5 h.Volatiles were evaporated and resulting solid was taken in ethyl acetateand washed with, brine (2 ml), a mixture of 5% KHSO₄ solution in brine(2 ml), dried over sodium sulfate, concentrated and purified bypreparative HPLC to give 13 mg ofN-[(3S,4R,5R,6S)-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-3,4,5-trihydroxy-tetrahydro-pyran-2-yl]-N-propyl-acetamide.¹H NMR (400 MHz, CD₃OD): δ 0.86 (t, J=7.2 Hz, 3H), 1.06-1.11 (m, 3H),1.56-1.64 (m, 2H), 1.93 (qui, J=6.4 Hz, 2H), 2.17 (s, 3H), 2.57-2.63 (m,2H), 2.68 (t, J=6.4 Hz, 2H), 3.00-3.17 (m, 1H), 3.33-3.36 (m, 1H),3.50-3.63 (m, 3H), 3.89 (s, 2H), 4.10 (t, J=4.8 Hz, 2H), 4.15-4.23 (m,1H), 4.95 (d, J=8.8 Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 6.75-6.80 (m, 2H),7.12-7.16 (m, 3H). MS (ES) m/z 484.3 (M+1).

The following examples could be prepared using the procedures describedin Examples 1-4 and the appropriate starting materials.

Ex. No. Structure Name 5-1

2S,3R,4R,5S,6R)-2-[4- Cyclopropyl-3-(2,3,4,5- tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6- methylsulfanyl-tetrahydro- pyran-3,4,5-triol 5-2

(2S,3R,4R,5S,6R)-2-[4- Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]thiepin- 7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro- pyran-3,4,5-triol 5-3

(2S,3R,4R,5S,6R)-2-[4- Ethyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)- phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol 5-4

(2S,3R,4R,5S,6R)-2-[4- Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin- 7-ylmethyl)-phenyl]-6-Zethylsulfanyl-tetrahydro- pyran-3,4,5-triol 5-5

(2S,3R,4R,5S,6R)-2-[4- Chloro-3-(2,3,4,5- tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6- methylsulfanyl-tetrahydro- pyran-3,4,5-triol 5-6

(2S,3R,4R,5S,6R)-2-[4- Methoxy-3-(2,3,4,5- tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6- methylsulfanyl-tetrahydro- pyran-3,4,5-triol 5-7

(2S,3R,4R,5S,6R)-2-[4- Cyclopentyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin- 7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro- pyran-3,4,5-triol 5-8

(2S,3R,4R,5S,6R)-2-[4- Cyclobutyl-3-(2,3,4,5-tetrahydro-benzo[b]thiepin- 7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro- pyran-3,4,5-triol 5-9

(2R,3S,4R,5R,6S)-2- Methylsulfanyl-6-[4-oxetan-3-yl-3-(2,3,4,5-tetrahydro- benzo[b]oxepin-7-ylmethyl)-phenyl]-tetrahydro-pyran- 3,4,5-triol 5-10

(2S,3R,4R,5S,6R)-2-[4- Cyclopropyl-3-(1,2,3,4- tetrahydro-quinolin-7-ylmethyl)-phenyl]-6- methanesulfonyl- tetrahydro-pyran-3,4,5-triol 5-11

(2S,3R,4R,5S,6R)-2-[4- Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6- ylmethyl)-phenyl]-6- methanesulfonyl-tetrahydro-pyran-3,4,5-triol 5-12

(2S,3R,4R,5S,6R)-2-(4- cyclopropyl-3-((3,4-dihydro-spiro[benzo[b][1,4]oxazine- 2,1′-cyclopropane]-6- yl)methyl)phenyl)-6-(methylsulfonyl)tetrahydro- 2H-pyran-3,4,5-triol 5-13

(2S,3R,4R,5S,6R)-2-[4- Cyclopropyl-3-(2-methyl- 3,4-dihydro-2H-benzo[1,4]oxazin-6- ylmethyl)-phenyl]-6- methanesulfonyl-tetrahydro-pyran-3,4,5-triol 5-14

(2S,3R,4R,5S,6R)-2-[4- Cyclopropyl-3-(1,1-dioxo- 1,2,3,4-tetrahydro-1lambda*6*- benzo[1,4]thiazin-6- ylmethyl)-phenyl]-6- methanesulfonyl-tetrahydro-pyran-3,4,5-triol 5-15

(2S,3R,4R,5S,6R)-2-[4- Cyclopentyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin- 7-ylmethyl)-phenyl]-6- methanesulfonyl-tetrahydro-pyran-3,4,5-triol 5-16

(2R,3S,4R,5R,6S)-2- Methanesulfonyl-6-[4- oxetan-3-yl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin- 7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol 5-17

(2S,3R,4R,5S,6S)-2-[3- (2,2-Dimethyl-3,4-dihydro- 2H-benzo[1,4]oxazin-6-ylmethyl)-4-ethyl-phenyl]-6- methoxy-tetrahydro-pyran- 3,4,5-triol 5-18

(2S,3R,4R,5S,6S)-2-[4- Ethyl-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)- phenyl]-6-methoxy- tetrahydro-pyran-3,4,5-triol5-19

(2S,3R,4R,5S,6S))-2-[4- Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]thiazin-6- ylmethyl)-phenyl]-6- methoxy-tetrahydro-pyran-3,4,5-triol 5-20

(2S,3R,4R,5S,6S)-2-[4- Cyclopropyl-3-(3,4-dihydro-2H-1,4-ethano-quinolin-7- ylmethyl)-phenyl]-6- methoxy-tetrahydro-pyran-3,4,5-triol 5-21

(2S,3R,4R,5S,6S)-2-[4- Ethyl-3-(1,2,3,4-tetrahydro-quinoxalin-6-ylmethyl)- phenyl]-6-methoxy- tetrahydro-pyran-3,4,5-triol5-22

6-[2-Cyclopropyl-5- ((2S,3R,4R,5S,6S)-3,4,5- trihydroxy-6-methoxy-tetrahydro-pyran-2-yl)- benzyl]-3,4-dihydro-2H- benzo[1,4]oxazine-2-carboxylic acid 5-23

6-[2-Cyclopropyl-5- ((2S,3R,4R,5S,6S)-3,4,5- trihydroxy-6-methoxy-tetrahydro-pyran-2-yl)- benzyl]-3,4-dihydro-2H- benzo[1,4]oxazine-2-carbonitrile 5-24

(2S,3R,4R,5S,6S)-2-[4- Cyclopropyl-3-(5- methylamino-5,6,7,8-tetrahydro-naphthalen-2- ylmethyl)-phenyl]-6- methoxy-tetrahydro-pyran-3,4,5-triol 5-25

(2S,3S,4R,5R,6S)-2- Methoxy-6-[4-oxetan-3-yl-3- (2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)- phenyl]-tetrahydro-pyran- 3,4,5-triol 5-26

(2S,3R,4R,5S,6S)-2-[4- Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin- 7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran- 3,4,5-triol 5-27

(2S,3R,4R,5S,6S)-2-[4- Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]thiepin- 7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran- 3,4,5-triol 5-28

(2S,3R,4R,5S,6S)-2-[4- Ethyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)- phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol 5-29

(2S,3R,4R,5S,6S)-2-[4- Chloro-3-(2,3,4,5- tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6- methoxy-tetrahydro-pyran- 3,4,5-triol 5-30

(2S,3R,4R,5S,6S)-2-[4- Cyclopropyl-3-(6,7,8,9- tetrahydro-5-oxa-9-aza-benzocyclohepten-3- ylmethyl)-phenyl]-6- methoxy-tetrahydro-pyran-3,4,5-triol 5-31

(2S,3R,4R,5S)-2-[3-(2,3- Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6- phenylsulfanyl-tetrahydro-pyran-3,4,5-triol 5-32

(2S,3R,4R,5S)-2-[3-(2,3- Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6- (thiophene-2-sulfonyl)-tetrahydro-pyran-3,4,5-triol 5-33

(3S,4R,5R,6S)-2- Cyclopropanesulfonyl-6-[3- (2,3-dihydro-benzo[1,4]dioxin-6- ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-3,4,5-triol 5-34

(2S,3R,4R,5S)-2-[3-(2,3- Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6- (2,2,2-trifluoro-ethanesulfonyl)-tetrahydro- pyran-3,4,5-triol 5-35

(2S,3R,4R,5S,6S)-2-[3- (2,2-Dimethyl-3,4-dihydro- 2H-benzo[1,4]oxazin-6-ylmethyl)-4-ethyl-phenyl]-6- methylamino-tetrahydro- pyran-3,4,5-triol5-36

(2S,3R,4R,5S,6S)-2-[4- Ethyl-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)- phenyl]-6-propylamino-tetrahydro-pyran-3,4,5-triol 5-37

(2S,3R,4R,5S,6S)-2-[3- (3,4-Dihydro-2H- benzo[1,4]oxazin-6-ylmethyl)-4-ethyl-phenyl]-6- propylamino-tetrahydro- pyran-3,4,5-triol5-38

N-{(2S,3S,4R,5R,6S)-6-[3- (3,4-Dihydro-2H- benzo[1,4]oxazin-6-ylmethyl)-4-ethyl-phenyl]- 3,4,5-trihydroxy-tetrahydro-pyran-2-yl}-acetamide 5-39

(2S,3S,4R,5R,6S)-2- Cyclopropylamino-6-[3-(3,4- dihydro-2H-benzo[1,4]oxazin-6- ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-3,4,5-triol 5-40

(2S,3R,4R,5S,6S)-2-[4- Ethyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)- phenyl]-6-methylamino-tetrahydro-pyran-3,4,5-triol 5-41

N-{(2S,3S,4R,5R,6S)-6-[4- Chloro-3-(2,3,4,5- tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-3,4,5- trihydroxy-tetrahydro-pyran- 2-yl}-acetamide5-42

(2S,3R,4R,5S,6S)-2-[4- Cyclopropyl-3-(6,7,8,9- tetrahydro-5-oxa-9-aza-benzocyclohepten-3- ylmethyl)-phenyl]-6- ethylamino-tetrahydro-pyran-3,4,5-triol 5-43

(2S,3R,4R,5S)-2-[4- Cyclopropyl-3-(2,3-dihydro- benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6- pyrrolidin-1-yl-tetrahydro- pyran-3,4,5-triol 5-44

(2S,3R,4R,5S)-2-[4- Cyclopropyl-3-(2,3-dihydro- benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6- morpholin-4-yl-tetrahydro- pyran-3,4,5-triol

The following are further embodiments of the invention:

Embodiment 1: A compound represented by structural formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

-   -   ring A is a 5-, 6- or 7-membered heterocyclyl;    -   X is O, NR⁵, S, S(O) or S(O)₂;    -   V is hydrogen, halo or —OR^(1b);    -   R¹, R^(1a) and R^(1b) are independently selected from the group        consisting of hydrogen, C₁₋₆ alkyl, C₆₋₁₀aryl-C₁₋₄alkyl,        C(O)C₆₋₁₀aryl and —C(O)C₁₋₆alkyl;    -   R² and R^(2a), for each occurrence, are independently selected        from the group consisting of halo, hydroxy, cyano, carboxy,        C₁₋₆alkyl, C₁₋₆alkoxy and C₃₋₁₀cycloalkyl;    -   R³ is halo, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₁₀cycloalkyl,        C₁₋₆alkoxy, haloC₁₋₃alkoxy or a 3- to 7-membered heterocyclyl;    -   R⁴ is a C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, or        a 5- to 10-membered heteroaryl;    -   R⁵ is hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, or C₁₋₆alkanoyl; or    -   R⁴ and R⁵ together with the nitrogen to which they are attached        form a 3- to 7-membered heterocyclyl;    -   n is 0, 1, 2, or 3; and    -   q is 0, 1, or 2.

Embodiment 2: The compound of Embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein the group represented by the followingformula:

is selected from the group consisting of:

Embodiment 3: The compound of Embodiment 1 or 2, or a pharmaceuticallyacceptable salt thereof, wherein the group represented by the followingformula:

is selected from the group consisting of:

Embodiment 4: The compound of anyone of the preceding embodiments, or apharmaceutically acceptable salt thereof, wherein the group representedby the following formula:

is selected from the group consisting of:

Embodiment 5: The compound of anyone of the preceding embodiments, or apharmaceutically acceptable salt thereof, wherein the group representedby the following formula:

Embodiment 6: The compound of anyone of Embodiments 1-3, or apharmaceutically acceptable salt thereof, wherein n is 0.

Embodiment 7: The compound of anyone of Embodiments 1-3 and 6, or apharmaceutically acceptable salt thereof, wherein q is 0.

Embodiment 8: The compound of anyone of the preceeding embodiments, or apharmaceutically acceptable salt thereof, wherein V is —OR^(1b).

Embodiment 9: The compound of anyone of the preceeding embodiments, or apharmaceutically acceptable salt thereof, wherein R¹, R^(1a), and R^(1b)are hydrogen.

Embodiment 10: The compound of anyone of the preceding embodiments, or apharmaceutically acceptable salt thereof, wherein R³ is halo, C₁₋₆alkyl,or C₃₋₁₀cycloalkyl.

Embodiment 11: The compound of anyone of the preceeding embodiments, ora pharmaceutically acceptable salt thereof, wherein R³ is bromo, ethylor cyclopropyl.

Embodiment 12:The compound of anyone of the preceeding embodiments, or apharmaceutically acceptable salt thereof, wherein R³ is ethyl.

Embodiment 13: The compound of anyone of the proceeding embodiments, ora pharmaceutically acceptable salt thereof, wherein X is O.

Embodiment 14: The compound of anyone of Embodiments 1-12, or apharmaceutically acceptable salt thereof, wherein X is S.

Embodiment 15: The compound of anyone of Embodiments 1-12, or apharmaceutically acceptable salt thereof, wherein X is S(O)₂.

Embodiment 16: The compound of anyone of Embodiments 1-12, or apharmaceutically acceptable salt thereof, wherein X is NR⁵.

Embodiment 17: The compound of anyone of the proceeding embodiments, ora pharmaceutically acceptable salt thereof, wherein R⁴ is C₁₋₄alkyl,haloC₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl, or a 5- to 6-membered heteroaryl.

Embodiment 18: The compound of anyone of the proceeding embodiments, ora pharmaceutically acceptable salt thereof, wherein R⁴ is methyl.

Embodiment 19: The compound of Embodiment 16, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is a C₁₋₆alkyl and R⁵ is aC₁₋₆alkanoyl.

Embodiment 20: The compound of Embodiment 19, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is n-propyl and R⁵ is acetyl.

Embodiment 21: The compound of Embodiment 16, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ and R⁵ together with the nitrogen towhich they are attached form a 5- to 6-membered heterocyclyl.

Embodiment 22: The compound of Embodiment 21, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ and R⁵ together with the nitrogen towhich they are attached form a pyrrolidino or a morpholino.

Embodiment 23: The compound of Embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound is selected from the groupconsisting of:

-   (2S,3R,4R,5S)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-isochroman-7-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Ethyl-3-isochroman-7-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methanesulfonyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methanesulfonyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   N-[(3S,4R,5R,6S)-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-3,4,5-trihydroxy-tetrahydro-pyran-2-yl]-N-propyl-acetamide;-   2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]thiepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol-   (2S,3R,4R,5S,6R)-2-[4-Ethyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-Zethylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Methoxy-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopentyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclobutyl-3-(2,3,4,5-tetrahydro-benzo[b]thiepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2R,3S,4R,5R,6S)-2-Methylsulfanyl-6-[4-oxetan-3-yl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-cyclopropyl-3-((3,4-dihydro-spiro[benzo[b][1,4]oxazine-2,1′-cyclopropane]-6-yl)methyl)phenyl)-6-(methylsulfonyl)tetrahydro-2H-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(1,1-dioxo-1,2,3,4-tetrahydro-1lambda*6*-benzo[1,4]thiazin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Cyclopentyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2R,3S,4R,5R,6S)-2-Methanesulfonyl-6-[4-oxetan-3-yl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[3-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-ethyl-phenyl]-6-methoxy-tetra    hydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Ethyl-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(3,4-dihydro-2H-1,4-ethano-quinolin-7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Ethyl-3-(1,2,3,4-tetrahydro-quinoxalin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   6-[2-Cyclopropyl-5-((2S,3R,4R,5S,6S)-3,4,5-tri    hydroxy-6-methoxy-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid;-   6-[2-Cyclopropyl-5-((2S,3R,4R,5S,6S)-3,4,5-tri    hydroxy-6-methoxy-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonitrile;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(5-methylamino-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3S,4R,5R,6S)-2-Methoxy-6-[4-oxetan-3-yl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(2,3,4,5-tetra    hydro-benzo[b]thiepin-7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Ethyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methoxy-tetra    hydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Chloro-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methoxy-tetra    hydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylmethyl)-phenyl]-6-methoxy-tetra    hydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-phenylsulfanyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-(thiophene-2-sulfonyl)-tetra    hydro-pyran-3,4,5-triol;-   (3S,4R,5R,6S)-2-Cyclopropanesulfonyl-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-3,4,5-triol;    and-   (2S,3R,4R,5S)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-(2,2,2-trifluoro-ethanesulfonyl)-tetrahydro-pyran-3,4,5-triol.

Embodiment 24: The compound of Embodiment 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound is selected from the groupconsisting of:

-   (2S,3R,4R,5S)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-isochroman-7-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Ethyl-3-isochroman-7-ylmethyl-phenyl)-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methanesulfonyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methanesulfonyl-tetrahydropyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;-   (2S,3R,4R,5S,6S)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;    and-   N-[(3S,4R,5R,6S)-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-3,4,5-trihydroxy-tetrahydro-pyran-2-yl]-N-propyl-acetamide.

Embodiment 25: A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound according to any one of Embodiments 1 to24, or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carrier.

Embodiment 26: A combination comprising a therapeutically effectiveamount of a compound according to any one of Embodiments 1 to 24, or apharmaceutically acceptable salt thereof, and one or moretherapeutically active co-agents.

Embodiment 27: A method of inhibiting sodium D-glucose co-transporteractivity in a subject, wherein the method comprises administering to thesubject a therapeutically effective amount of the compound according toany one of Embodiments 1 to 24, or a pharmaceutically acceptable saltthereof.

Embodiment 28: A method of treating diabetes comprising administering acompound according to any one of Embodiments 1 to 24, or apharmaceutically acceptable salt thereof, to a subject in need thereof.

Embodiment 29: A method of treating a disease or condition mediated bythe sodium D-glucose co-transporter in a subject, comprisingadministering to the mammal in need thereof a therapeutically effectiveamount of a compound according to any one of Embodiments 1 to 24, or apharmaceutically acceptable salt thereof.

Embodiment 30: The method according to Embodiment 29, wherein thedisease or condition is metabolic syndrome, Syndrome X, diabetes,insulin resistance, decreased glucose tolerance, non-insulin-dependentdiabetes mellitus, Type II diabetes, Type I diabetes, diabeticcomplications, a body weight disorder, obesity, or a leptin relateddisease.

Embodiment 31: The method according to Embodiment 30, wherein thedisease or condition is dyslipidemia, obesity, insulin resistance,hypertension, microalbuminemia, hyperuricaemia, or hypercoagulability.

Embodiment 32: A compound of any one of Embodiments 1 to 24, or apharmaceutically acceptable salt thereof, for use as a medicament.

Embodiment 33: A compound of any one of Embodiments 1 to 24, or apharmaceutically acceptable salt thereof, for use in treating diabetes.

Embodiment 34: A compound of any one of Embodiments 1 to 24, or apharmaceutically acceptable salt thereof, for use in treating a diseaseor condition in a subject mediated by sodium D-glucose co-transporter.

Embodiment 35: The compound according to Embodiment 34, or apharmaceutically acceptable salt thereof, wherein the disease orcondition is metabolic syndrome, Syndrome X, diabetes, insulinresistance, decreased glucose tolerance, non-insulin-dependent diabetesmellitus, Type II diabetes, Type I diabetes, diabetic complications, abody weight disorder, obesity, or a leptin related disease.

Embodiment 36: The compound according to Embodiment 35, or apharmaceutically acceptable salt thereof, wherein the disease orcondition is dyslipidemia, obesity, insulin resistance, hypertension,microalbuminemia, hyperuricaemia, or hypercoagulability.

Embodiment 37: Use of a compound according to any one of Embodiments 1to 24, or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for the treatment of diabetes.

Embodiment 38: Use of a compound according to any one of Embodiments 1to 24, or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for the treatment of a disorder or disease mediated bysodium D-glucose co-transporter.

Embodiment 39: Use of a compound according to Embodiment 38, or apharmaceutically acceptable salt thereof, wherein the disease orcondition ismetabolic syndrome, Syndrome X, diabetes, insulinresistance, decreased glucose tolerance, non-insulin-dependent diabetesmellitus, Type II diabetes, Type I diabetes, diabetic complications, abody weight disorder, obesity, or a leptin related disease.

Embodiment 40: Use of a compound according to Embodiment 39, or apharmaceutically acceptable salt thereof, wherein the disease orcondition is dyslipidemia, obesity, insulin resistance, hypertension,microalbuminemia, hyperuricaemia, or hypercoagulability.

Embodiment 41: A pharmaceutical compositions comprising atherapeutically effective amount of a compound according to any one ofEmbodiments 1 to 24, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of anothertherapeutic agent.

Embodiment 42: A pharmaceutical combination comprising:

-   -   i) a compound according to any one of Embodiments 1 to 24, or a        pharmaceutically acceptable salt thereof,    -   ii) at least one compound selected from        -   a) antidiabetic agents,        -   b) hypolipidemic agents,        -   c) anti-obesity agents,        -   d) anti-hypertensive agents,        -   e) agonists of peroxisome proliferator-activator receptors.

The invention claimed is:
 1. A compound represented by structuralformula (I):

or a pharmaceutiacally acceptable salt thereof, wherein: ring A is a 5-,6- or 7-membered heterocyclyl; X is O, NR⁵, S, S(O) or S(O)₂; V ishydrogen, halo or —OR^(1b); R¹, R¹a and R^(1b) are independentlyselected from the group consisting of hydrogen, C₁-₆ alkyl,C₆₋₁₀aryl-—₁₋₄alkyl, —C(O)C₆₋₁₀aryl and —C(O)C₁₋₆alkyl1kyl; R² and R²a,for each occurrence, are independently selected from the groupconsisting of halo, hydroxy, cyano, carboxy, C₁₋₆alkyl, C₁₋₆alkoxy andC₃₋₁₀cycloalkyl; R³ is halo, hydroxy, C₁₋₆alkyl, haloC₁₋₆alkyl,C₃₋₁₀cycloalkyl, C₁₋₆alkoxy, haloC₁₋₃alkoxy or a 3- to 7-memberedheterocyclyl; R⁴ is a C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₆₋₁₀aryl, or a 5- to 10-membered heteroaryl; R⁵ is hydrogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl, or C₁₋₆alkanoyl; or R⁴ and R⁵ together with thenitrogen to which they are attached form a 3- to 7-memberedheterocyclyl; n is 0, 1, 2, or 3; and q is 0, 1, or
 2. 2. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein thegroup represented by the following formula:

is selected from the group consisting of:


3. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the group represented by the following formula:

is selected from the group consisting of:


4. The compound of anyone of claim 1, or a pharmaceutically acceptablesalt thereof, wherein the group represented by the following formula:

is selected from the group consisting of:


5. The compound of anyone of claim 1, or a pharmaceutically acceptablesalt thereof, wherein the group represented by the following formula:


6. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein n is
 0. 7. The compound of anyone of claim 1, or apharmaceutically acceptable salt thereof, wherein q is
 0. 8. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein V is —OR^(1b).
 9. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹, R¹a, and R^(1b) are hydrogen. 10.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is halo, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl.
 11. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R³ isbromo, ethyl or cyclopropyl.
 12. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R³ is ethyl.
 13. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁴ and R⁵ together with the nitrogen to which they are attachedform a pyrrolidino or a morpholino.
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:(2S,3R,4R,5S)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4ethyl-phenyl)-6methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methylsulfanyltetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-Bromo-3-isochroman-7-ylmethyl-phenyl)-6methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-Ethyl-3-isochroman-7-ylmethyl-phenyl)-6-methylsulfanyltetrahydropyran-3,4,5-triol;(2S,3R,4R,5S)-2-[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methanesulfonyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6methanesulfonyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;N-[-3S,4R,5R,6S)-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-3,4,5-trihydroxy-tetrahydro-pyran-2-yl]-N-propyl-acetamide;2S,3R,4R,5S,6R)-2[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]thiepin-7-ylmethyl)phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol(2S,3R,4R,5S,6R)-2-[4-Ethyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6methylsulfanyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-Zethylsulfanyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-Methoxy-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2[4-Cyclopentyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7ylmethyl-phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-Cyclobutyl-3-(2,3,4,5-tetrahydro-benzo[b]thiepin-7-ylmethyl)phenyl]-6-methylsulfanyl-tetrahydro-pyran-3,4,5-triol;(2R,3S,4R,5R,6S)-2-Methylsulfanyl-6[4-oxetan-3-yl-3-(2,3,4,5-tetrahydrobenzo[b]oxepin-7-ylmethyl)-phenyl]tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2[4-Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-cyclopropyl-3-((3,4-dihydro-spiro[benzo[b][1,4]oxazine-2,1′-cyclopropane]-6-yl)methyl)phenyl)-6-(methylsulfonyl)tetrahydro-2H-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2[4-Cyclopropyl-3-(2-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-Cyclopropyl-3-(1,1-dioxo-1,2,3,4-tetrahydro-11ambda*6*-benzo[1,4]thiazin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2[4-Cyclopentyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2R,3S,4R,5R,6S)-2-Methanesulfonyl-644-oxetan-3-yl-3-(2,3,4,5tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenylHetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-[4-(2,2-Dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4ethyl-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-[4-Ethyl-3-(1,2,3,4-tetrahydro-quinolin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2[4-Cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]thiazin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(3,4-dihydro-2H-1,4-ethano-quinolin-7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-[4--Ethyl-3-(1,2,3,4-tetrahydro-quinoxalin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;6[2-Cyclopropyl-5-((2S,3R,4R,5S,6S)-3,4,5-trihydroxy-6-methoxy-tetrahydro-pyran-2y1)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid;6[2-Cyclopropyl-5-((2S,3R,4R,5S,6S)-3,4,5-trihydroxy-6-methoxy-tetrahydro-pyran-2y1)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine-2-carbonitrile;(2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(5-methylamino-5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3S,4R,5R,6S)-2-Methoxy-644-oxetan-3-yl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenylHetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(2,3,4,5-tetrahydro-benzo[b]thiepin-7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-[4-Ethyl-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-[4-Chloro-3-(2,3,4,5-tetrahydro-benzo[b]oxepin-7-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-[4-Cyclopropyl-3-(6,7,8,9-tetrahydro-5-oxa-9aza-benzocyclohepten-3-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S)-2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-phenylsulfanyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S)-2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-(thiophene-2-sulfonyl)-tetrahydro-pyran-3,4,5-triol;(3S,4R,5R,6S)-2-Cyclopropanesulfonyl-643-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenylHetrahydro-pyran-3,4,5-triol;and(2S,3R,4R,5S)-2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-(2,2,2-trifluoro-ethanesulfonyl)-tetrahydro-pyran-3,4,5-triol.15. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is selected from the group consisting of:(2S,3R,4R,5S)-2-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4ethyl-phenyl)-6methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyI)-6methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-Bromo-3-isochroman-7-ylmethyl-phenyI)-6methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-Ethyl-3-isochroman-7-ylmethyl-phenyl)-6methylsulfanyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S)-2-[4-Cyclopropyl-3-(2,3dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methanesulfonyl-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6methanesulfonyl-tetrahydropyran-3,4,5-triol; (2S,3R,4R,5S,6R)-2-[4-Bromo-3-(2,3dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6R)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyI)-6methanesulfonyl-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2[4-Cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-(4-Bromo-3-chroman-6-ylmethyl-phenyI)-6-methoxy-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-ethyl-phenyl)-6-methoxy-tetrahydropyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-(3-Chroman-6-ylmethyl-4-cyclopropyl-phenyl)-6-methoxytetrahydro-pyran-3,4,5-triol;(2S,3R,4R,5S,6S)-2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol;andN-[(3S,4R,5R,6S)-6-(3-chroman-6-ylmethyl-4-ethyl-phenyl)-3,4,5-trihydroxy-tetrahydro-pyran-2-yl]-N-propyl-acetamide.
 16. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound according toclaim 1, or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carrier.
 17. A method of treating a diseaseor condition in a subject wherein the disease or condition is selectedfrom Syndrome X, diabetes, insulin resistance, decreased glucosetolerance, non-insulin-dependent diabetes mellitus, Type II diabetes,Type I diabetes, dyslipidemia, obesity, hypertension, microalbuminemiaand disorders arising from hyperglycemia, comprising administering tothe mammal in need thereof a therapeutically effective amount of acompound according to claim 1, or a pharmaceutically acceptable saltthereof.
 18. A pharmaceutical combination comprising: i) a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, ii)at least one compound selected from a) antidiabetic agents, b)hypolipidemic agents, c) anti-obesity agents, d) anti-hypertensiveagents, e) agonists of peroxisome proliferator-activator receptors.